GLP-1 receptor modulators

ABSTRACT

Compounds are provided that modulate the glucagon-like peptide 1 (GLP-1) receptor, as well as methods of their synthesis, and methods of their therapeutic and/or prophylactic use. Such compounds can act as modulators or potentiators of GLP-1 receptor on their own, or with incretin peptides such as GLP-1(7-36), GLP-1(9-36), and oxyntomodulin, or with peptide-based therapies, such as exenatide and liraglutide, and have the following general structure (where “ ” represents either or both the R and S form of the compound): 
                         
where A, B, C, R 1 , R 2 , R 3 , R 4 , R 5 , n, p and q are as defined herein.

FIELD OF THE INVENTION

The invention relates to compounds that bind the glucagon-like peptide 1(GLP-1) receptor, methods of their synthesis, and methods of theirtherapeutic and/or prophylactic use. The present invention is directedto compounds adapted to act as modulators of the GLP-1 receptor, andpotentiators of incretin peptides, such as GLP-1(7-36), GLP-1(9-36), andoxyntomodulin, as well as peptide-based therapies such as exenatide andliraglutide.

BACKGROUND

Glucagon-like peptide 1 receptor (GLP-1R) belongs to Family B1 of theseven-transmembrane G protein-coupled receptors, and its natural agonistligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 isa peptide hormone arising by its alternative enzymatic cleavage fromproglucagon, the prohormone precursor for GLP-1, which is highlyexpressed in enteroendocrine cells of the intestine, the alpha cells ofthe endocrine pancreas (islets of Langerhans), and the brain (Kieffer T.J. and Habener, J. F. Endocrin. Rev. 20:876-913 (1999); Drucker, D. J.,Endocrinology 142:521-7 (2001); Holst, J. J., Diabetes Metab. Res. Rev.18:430-41 (2002)). The initial actions of GLP-1 observed were on theinsulin-producing cells of the islets, where it stimulatesglucose-dependent insulin secretion. Subsequently, multiple additionalantidiabetogenic actions of GLP-1 were discovered including thestimulation of the growth and inhibition of the apoptosis of pancreaticbeta cells (Drucker, D. J., Endocrinology 144:5145-8 (2003); Holz, G. G.and Chepurny O. G., Curr. Med. Chem. 10:2471-83 (2003); List, J. F. andHabener, J. F., Am. J. Physiol. Endocrinol. Metab. 286:E875-81 (2004)).

Like GLP-1, Oxyntomodulin is also generated from L-cell derivedproglucagon by alternative proteolysis. Oxyntomodulin is identical toglucagon plus an additional 8 amino acid carboxyterminal extension(Bataille D., et al, Peptides 2 Suppl s:41-4 (1981)). Oxyntomodulin is adual agonist of both GLP-1 receptor and glucagon receptor. Oxyntomodulininduces glucose dependent insulin secretion from pancreatic β cells(Maida, A., et al, Endocrinology 149:5670-8 (2008), and in vivo,oxyntomodulin modulates food intake (Dakin, C. L. et al, Endocrinology142:4244-50 (2001)) and is significantly anorectic (Baggio, L. L. et al,Gastroenterology 127:46-58 (2004)).

On activation, GLP-1 receptors couple to the α-subunit of G protein,with subsequent activation of adenylate cyclase and increase of cAMPlevels, thereby potentiating glucose-stimulated insulin secretion.Therefore, GLP-1 is an attractive therapeutic target to lower bloodglucose and preserve the β-cells of the pancreas of diabetic patients.Glucagon has been used for decades in medical practice within diabetesand several glucagon-like peptides are being developed for varioustherapeutic indications. GLP-1 analogs and derivatives are beingdeveloped for the treatment for patients suffering from diabetes.

SUMMARY OF THE INVENTION

The present invention is directed to compounds adapted to act aspotentiators or modulators of GLP-1 receptor; methods of theirpreparation and methods of their use, such as in treatment of amalcondition mediated by GLP-1 receptor activation, or when modulationor potentiation of GLP-1 receptor is medically indicated.

Certain embodiments of the present invention comprise a compound havingthe structure of Formula I-R or I-S or a pharmaceutically acceptableisomer, enantiomer, racemate, salt, isotope, prodrug, hydrate or solvatethereof:

wherein

A is pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl, each of which maybe optionally substituted with one or more of R₄;

B is phenyl or heterocycle;

C is a nonaromatic carbocyclyl or nonaromatic carbocyclylalkyl;

each R₁ is independently H or C₁₋₄ alkyl;

R₂ is —OH, —O—R₈, —N(R₁)—SO₂—R₇, —NR₄₁R₄₂,—N(R₁)—(CR_(a)R_(b))_(m)—COOR₈, —N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)(R₄₀),—N(R₁)—(CR_(a)R_(b))_(m)—N(R₁)C(O)O(R₈),—N(R₁)—(CR_(a)R_(b))_(m)—N(R₁)(R₄₀),—N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl, or—N(R₁)—(CR_(a)R_(b))_(m)-heterocyclyl, which heterocyclyl may beoptionally (singly or multiply) substituted with R₇;

each R₃ and R₄ is independently H, halo, alkyl, alkyl substituted(singly or multiply) with R₃₁, alkoxy, haloalkyl, perhaloalkyl,haloalkoxy, perhaloalkoxy, aryl, heterocyclyl, —OH, —OR₇, —CN, —NO₂,—NR₁R₇, —C(O)R₇, —(O)NR₁R₇, —NR₁C(O)R₇, —SR₇, —S(O)R₇, —S(O)₂R₇,—OS(O)₂R₇, —S(O)₂NR₁R₇, —NR₁S(O)₂R₇, —(CR_(a)R_(b))_(m)NR₁R₇,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₇,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₇ or—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)COOR₈; or any two R₃ or R₄ groupson the same carbon atom taken together form oxo;

R₅ is R₇, —(CR_(a)R_(b))_(m)—(CR_(a)R_(b))_(m)—R₇, or-(-L₃-(CR_(a)R_(b))_(r)-L₃-R₇, wherein the carbon atoms of any twoadjacent —(CR_(a)R_(b))_(m) or (CR_(a)R_(b))_(r) groups may be takentogether to form a double bond (—(C(R_(a))═(C(R_(a))—) or triple bond(—C≡C—);

R₆ is H, alkyl, aryl, heteroaryl, heterocyclyl, heterocycloalkyl, any ofwhich may be optionally substituted (singly or multiply) with R₇ or—(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₇;

each R₇ is independently R₁₀; a ring moiety selected from cycloalkyl,aryl, aralkyl, heterocyclyl or heterocyclylalkyl, where such ring moietyis optionally (singly or multiply) substituted with R₁₀; or when acarbon atom bears two R₇ groups such two R₇ groups are taken together toform oxo or thioxo, or are taken together (when attached to the samecarbon atom or different carbon atoms) to form a ring moiety selectedfrom cycloalkyl, aryl, heterocyclyl or heterocyclylalkyl, wherein suchring moiety is optionally singly or multiply substituted with R₁₀;

each R₈ is independently H, alkyl, haloalkyl, aryl,—(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₁ or-(-L₃-(CR_(a)R_(b))_(r)—)_(s)-L₃-R₁;

each R₁₀ is independently H, halo, alkyl, haloalkyl, haloalkoxy,perhaloalkyl, perhaloalkoxy, —(CR_(a)R_(b))_(m)OH,—(CR_(a)R_(b))_(m)OR₈, —(CR_(a)R_(b))_(m)CN,—(CR_(a)R_(b))_(m)NH(C═NH)NH₂, —(CR_(a)R_(b))_(m)NR₁R₈,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₈, —(CR_(a)R_(b))_(m)C(O)R₈,—(CR_(a)R_(b))_(m)C(O)OR₈, —(CR_(a)R_(b))_(m)C(O)NR₁R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)C(O)OR₈,—CR_(a)R_(b))_(m)NR₁C(O)R₈, —(CR_(a)R_(b))_(m)C(O)NR₁S(O)₂R₈,—(CR_(a)R_(b))_(m)SR₈, —(CR_(a)R_(b))_(m)S(O)R₈,CR_(a)R_(b))_(m)S(O)₂R₈, —(CR_(a)R_(b))_(m)S(O)₂NR₁R₈ or—(CR_(a)R_(b))_(m)NR₁S(O)₂R₈;

each R₃₁ is independently H, halo, hydroxyl, —NR₄₁R₄₂, or alkoxy;

each R₄₀ is independently H, R₇, alkyl which may be optionally (singlyor multiply) substituted with R₇, or R₄₀ and R₁ taken together with theN atom to which they are attached form a 3- to 7-membered heterocyclylwhich may be optionally (singly or multiply) substituted with R₇;

each R₄₁ and R₄₂ is independently R₄₀, —(CHR₄₀)_(n)—C(O)O—R₄₀,—(CHR₄₀)_(n)—C(O)—R₄₀, —(CH₂)_(n)—N(R₁)(R₇), aryl or heteroaryl any ofwhich aryl or heteroaryl may be optionally (singly or multiply)substituted with R₇; or any two R₄₁ and R₄₂ taken together with the Natom to which they are attached form a 3- to 7-membered heterocyclylwhich may be optionally (singly or multiply) substituted with R₇;

each R_(a) and R_(b) is independently H, halo, alkyl, alkoxy, aryl,aralkyl, heterocyclyl, heterocyclylalkyl (any of which alkyl, alkoxy,aryl, aralkyl, heterocyclyl or heterocyclylalkyl may be optionally(singly or multiply) substituted with R₇), —(CHR₄₀)_(m)C(O)OR₄₀,—(CHR₄₀)_(m)OR₄₀, —(CHR₄₀)_(m)SR₄₀, —(CHR₄₀)_(m)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)—(CHR₄₀)_(m)C(O)OR₄₀, or —(CHR₄₀)_(m)—S—S—R₄₀; orany two R_(a) and R_(b) taken together with the carbon atom(s) to whichthey are attached form a cycloalkyl or heterocyclyl optionallysubstituted (singly or multiply) with R₇; or R₁ and any one of R_(a) orR_(b) taken together with the atoms to which they are attached formheterocyclyl optionally substituted (singly or multiply) with R₇;

L₂ is independently, from the proximal to distal end of the structure ofFormula I-R or I-S, null, —O—, —OC(O)—, —NR₁—, —C(O)NR₁—, —N(R₁)—C(O)—,—S(O₂)—, —S(O)—, —S—, —C(O)— or —S(O₂)—N(R₁)—;

each L₃ is independently null, —O—, or —N(R₁)—

each m is independently 0, 1, 2, 3, 4, 5 or 6;

each n is independently 0 or 1 or 2;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

each r is independently 2, 3, or 4; and

each s is independently 1, 2, 3, or 4.

In certain embodiments, a pharmaceutical composition comprising acompound of the invention together with at least one pharmaceuticallyacceptable carrier, diluent or excipient is provided.

In certain embodiments, a method of use of a compound of the inventioncomprising preparation of a medicament is provided.

In certain embodiments, the invention provides a pharmaceuticalcombination comprising a compound of the invention and a secondmedicament. In various such embodiments, the second medicament is anagonist or modulator for glucagon receptor, GIP receptor, GLP-2receptor, or PTH receptor, or glucagon-like peptide 1 (GLP-1) receptor.In various such embodiments, the second medicament is exenatide,liraglutide, taspoglutide, albiglutide, or lixisenatide or other insulinregulating peptide. In various embodiments, the second medicament ismedically indicated for the treatment of type II diabetes. In variousembodiments, the second medicament is a biguanide, a sulfonylurea, ameglitinide, a thiazolidinedione, an ca-glucosidase inhibitor, a bileacid sequestrant, an SGLT inhibitor, and/or a dopamine-2 agonist, and inmore specific embodiments is metformin (a biguanide), sitagliptin (aDPPIV inhibitor), or canagliflozin, dapagliflozin or empagliflozin (anSGLT inhibitor).

In certain embodiments, a method of activation, potentiation or agonismof a GLP-1 receptor is provided comprising contacting the receptor witha compound, pharmaceutical composition or pharmaceutical combination ofthe invention.

In certain embodiments, a method is provided for treatment of amalcondition in a subject for which activation, potentiation or agonismof a GLP-1 receptor is medically indicated where such method comprisesadministering to such subject a compound, pharmaceutical composition orpharmaceutical combination of the invention. In various suchembodiments, selective activation, potentiation or agonism of a GLP-1receptor, is medically indicated. In various such embodiments, themalcondition comprises type I diabetes, type II diabetes, gestationaldiabetes, obesity, excessive appetite, insufficient satiety, ormetabolic disorder.

In certain embodiments, the invention provides methods for synthesis ofcertain compounds including compounds of the invention. In certain otherembodiments, the invention provides certain intermediate compoundsassociated with such methods of synthesis.

DETAILED DESCRIPTION OF THE INVENTION

Certain embodiments comprise a compound having the chiral structure ofFormula I-R or I-S (with the chirality as indicated) or apharmaceutically acceptable isomer, enantiomer, racemate, salt, isotope,prodrug, hydrate or solvate thereof:

Certain embodiments of the present invention comprise a compound havingthe structure of Formula I-R or I-S or a pharmaceutically acceptableisomer, enantiomer, racemate, salt, isotope, prodrug, hydrate or solvatethereof:

where A, B, C, R₁, R₂, R₃, R₄, R₅, n, p and q are as defined above.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where B is phenyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where B is heterocyle.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where B is thiophenyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where B is pyrimidinyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where B is pyrazolyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where B is pyridinyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where B is indolyl.

Certain embodiments of the present invention comprise a compound havingthe structure of Formula I-R or I-S or a pharmaceutically acceptableisomer, enantiomer, racemate, salt, isotope, prodrug, hydrate or solvatethereof:

wherein

A is pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl, each of which maybe optionally substituted with one or more of R₄;

B is phenyl or thiophenyl;

C is a nonaromatic carbocyclyl or nonaromatic carbocyclylalkyl;

each R₁ is independently H or C₁₋₄ alkyl;

R₂ is —OH, —O—R₈, —N(R₁)—SO₂—R₇, —NR₄₁R₄₂,—N(R₁)—(CR_(a)R_(b))_(m)—COOR₈, —N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)(R₄₀),—N(R₁)—(CR_(a)R_(b))_(m)—N(R₁)C(O)O(R₈),—N(R₁)—(CR_(a)R_(b))_(m)—N(R₁)(R₄₀),—N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl, or—N(R₁)—(CR_(a)R_(b))_(m)-heterocyclyl, which heterocyclyl may beoptionally (singly or multiply) substituted with R;

each R₃ and R₄ is independently H, halo, alkyl, alkyl substituted(singly or multiply) with R₃₁, alkoxy, haloalkyl, perhaloalkyl,haloalkoxy, perhaloalkoxy, aryl, heterocyclyl, —OH, —OR₇, —CN, —NO₂,—NR₁R₇, —C(O)R₇, —(O)NR₁R₇, —NR₁C(O)R₇, —SR₇, —S(O)R₇, —S(O)₂R₇,—OS(O)₂R₇, —S(O)₂NR₁R₇, —NR₁S(O)₂R₇, —(CR_(a)R_(b))_(m)NR₁R₇,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₇,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₇ or—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)COOR₈; or any two R₃ or R₄ groupson the same carbon atom taken together form oxo;

R₅ is R₇, —(CR_(a)R_(b))_(m)—(CR_(a)R_(b))_(m)—R₇, or-(-L₃-(CR_(a)R_(b))_(r)-L₃-R₇, wherein the carbon atoms of any twoadjacent —(CR_(a)R_(b))_(m) or (CR_(a)R_(b))_(r) groups may be takentogether to form a double bond (—(C(R_(a))═(C(R_(a))—) or triple bond(—C≡C—);

R₆ is H, alkyl, aryl, heteroaryl, heterocyclyl, heterocycloalkyl, any ofwhich may be optionally substituted (singly or multiply) with R₇ or—(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₇;

each R₇ is independently R₁₀; a ring moiety selected from cycloalkyl,aryl, aralkyl, heterocyclyl or heterocyclylalkyl, where such ring moietyis optionally (singly or multiply) substituted with R₁₀; or when acarbon atom bears two R₇ groups such two R₇ groups are taken together toform oxo or thioxo, or are taken together to form a ring moiety selectedfrom cycloalkyl, aryl, heterocyclyl or heterocyclylalkyl, wherein suchring moiety is optionally singly or multiply substituted with R₁₀;

each R₈ is independently H, alkyl, haloalkyl, aryl,—(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₁ or-(-L₃-(CR_(a)R_(b))_(r)—)_(s)-L₃-R₁;

each R₁₀ is independently H, halo, alkyl, haloalkyl, haloalkoxy,perhaloalkyl, perhaloalkoxy, —(CR_(a)R_(b))_(m)OH,—(CR_(a)R_(b))_(m)OR₈, —(CR_(a)R_(b))_(m)CN,—(CR_(a)R_(b))_(m)NH(C═NH)NH₂, —(CR_(a)R_(b))_(m)NR₁R₈,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₈, —(CR_(a)R_(b))_(m)C(O)R₈,—(CR_(a)R_(b))_(m)C(O)OR₈, —(CR_(a)R_(b))_(m)C(O)NR₁R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)C(O)OR₈,—(CR_(a)R_(b))_(m)NR₁C(O)R₈, —(CR_(a)R_(b))_(m)C(O)NR₁S(O)₂R₈,—(CR_(a)R_(b))_(m)SR₈, —(CR_(a)R_(b))_(m)S(O)R₈,—(CR_(a)R_(b))_(m)S(O)₂R₈, —(CR_(a)R_(b))_(m)S(O)₂NR₁R₈ or—(CR_(a)R_(b))_(m)NR₁S(O)₂R₈;

each R₃₁ is independently H, halo, hydroxyl, —NR₄₁R₄₂, or alkoxy;

each R₄₀ is independently H, R₇, alkyl which may be optionally (singlyor multiply) substituted with R₇, or R₄₀ and R₁ taken together with theN atom to which they are attached form a 3- to 7-membered heterocyclylwhich may be optionally (singly or multiply) substituted with R₇;

each R₄₁ and R₄₂ is independently R₄₀, —(CHR₄₀)_(n)—C(O)O—R₄₀,—(CHR₄₀)_(n)—C(O)—R₄₀, —(CH₂)_(n)—N(R₁)(R₇), aryl or heteroaryl any ofwhich aryl or heteroaryl may be optionally (singly or multiply)substituted with R₇; or any two R₄₁ and R₄₂ taken together with the Natom to which they are attached form a 3- to 7-membered heterocyclylwhich may be optionally (singly or multiply) substituted with R₇;

each R_(a) and R_(b) is independently H, halo, alkyl, alkoxy, aryl,aralkyl, heterocyclyl, heterocyclylalkyl (any of which alkyl, alkoxy,aryl, aralkyl, heterocyclyl or heterocyclylalkyl may be optionally(singly or multiply) substituted with R₇), —(CHR₄₀)_(m)C(O)OR₄₀,—(CHR₄₀)_(m)OR₄₀, —(CHR₄₀)_(m)SR₄₀, —(CHR₄₀)_(m)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)—(CHR₄₀)_(m)C(O)OR₄₀, or —(CHR₄₀)_(m)—S—S—R₄₀; orany two R_(a) and R_(b) taken together with the carbon atom(s) to whichthey are attached form a cycloalkyl or heterocyclyl optionallysubstituted (singly or multiply) with R₇; or R₁ and any one of R_(a) orR_(b) taken together with the atoms to which they are attached formheterocyclyl optionally substituted (singly or multiply) with R₇;

L₂ is independently, from the proximal to distal end of the structure ofFormula I-R or I-S, null, —O—, —OC(O)—, —NR₁—, —C(O)NR₁—, —N(R₁)—C(O)—,—S(O₂)—, —S(O)—, —S—, —C(O)— or —S(O₂)—N(R₁)—;

each L₃ is independently null, —O—, or —N(R₁)—

each m is independently 0, 1, 2, 3, 4, 5 or 6;

each n is independently 0 or 1 or 2;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

each r is independently 2, 3, or 4; and

each s is independently 1, 2, 3, or 4.

In certain embodiments, the compounds have the structure of Formula I-Ror a pharmaceutically acceptable isomer, enantiomer, salt, isotope,prodrug, hydrate or solvate thereof. In other embodiments, the compoundshave the structure of Formula I-S or a pharmaceutically acceptableisomer, enantiomer, salt, isotope, prodrug, hydrate or solvate thereof.

In certain embodiments, the compounds can be substantiallyenantiomerically pure.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where A is pyrimidinyl optionally substituted withone or more of R₄. Representative compounds of this embodiment includecompounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where A is pyridinyl optionally substituted with oneor more of R₄. Representative compounds of this embodiment includecompounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where A is pyridazinyl optionally substituted withone or more of R₄. Representative compounds of this embodiment includecompounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where A is pyrazinyl optionally substituted with oneor more of R₄. Representative compounds of this embodiment includecompounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(5) where B is pyrimidinyl, pyrazolyl, pyridinyl orindolyl, and in further embodiments the invention provides compounds ofeach of structures I-R/S (1)-(5) where the B group is:

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(5) where the B group is phenyl. Representativecompounds of this embodiment include compounds of the followingstructures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (7)-(9) where n is 0 or 1. Representative compounds ofthis embodiment include compounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(3) where the B group is thiophenyl. Representativecompounds of this embodiment include compounds of the followingstructures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (13)-(15) where the B group is thiophen-2-yl.Representative compounds of this embodiment include compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (16)-(18) where n is 0 or 1. Representative compoundsof this embodiment include compounds of the following structures(wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(21) where the C group is nonaromatic carbocyclyl.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(21) where the C group is cycloalkyl.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(21) where the C group is cycloalkenyl.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(21) where the C group is nonaromaticcarbocyclylalkyl.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(21) where the C group is cycloalkylalkyl.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(21) where the C group is cycloalkenylalkyl.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(21) where the C group is:

In certain embodiments, the invention provides compounds of structuresI-R/S (22)-(23):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(23) where R₁ is H.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(23) where R₄ is H.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(23) where q is zero.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(23) where q is one, two or three.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S (1)-(23) where q is one.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(23) where q is one and R₅ is—(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₇ or-(-L₃-(CR_(a)R_(b))_(r)—)_(s)-L₃-R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(23) where q is one and R₅ is R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(23) where q is one and R₅ is R₇ and R₇ is halo, alkyl,haloalkyl, perhaloalkyl, alkoxy, —(CR_(a)R_(b))_(m)OH,—(CR_(a)R_(b))_(m)OR₈, —(CR_(a)R_(b))_(m)CN,—(CR_(a)R_(b))_(m)NH(C═NH)NH₂, —(CR_(a)R_(b))_(m)NR₁R₈,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)O(—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₈,—(CR_(a)R_(b))_(m)C(O)R₈, —(CR_(a)R_(b))_(m)C(O)OR₈,—(CR_(a)R_(b))_(m)C(O)NR₁R₈,—(CR_(a)R_(b))_(m)NR(CR_(a)R_(b))_(m)C(O)OR₈,—(CR_(a)R_(b))_(m)NR₁C(O)R₈, —(CR_(a)R_(b))_(m)C(O)NR₁R₈,—(CR_(a)R_(b))_(m)SR₈, —(CR_(a)R_(b))_(m)S(O)R₈,—(CR_(a)R_(b))_(m)S(O)₂R₈, —(CR_(a)R_(b))_(m)S(O)₂NR₁R₈,—(CR_(a)R_(b))_(m)NR₁S(O)₂R₈.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(23) where q is one and R₅ is R₇ and R₇ is a ring moietyselected from cycloalkyl, aryl, aralkyl, heterocyclyl orheterocyclylalkyl, where such ring moiety is optionally (singly ormultiply) substituted with halo, —OH, —CN, alkyl, alkoxy, haloalkyl orperhaloalkyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(23) where q is one and R₅ is R₇ and R₇ is a ring moietyselected from cycloalkyl singly substituted with alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(23) where q is one and R₅ is R₇ and R₇ is a ring moietyselected from cycloalkyl singly substituted with a linear C₃₋₆alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(23) where p is one and R₃ is halo, alkyl, alkyl substitutedwith R₃₁, alkoxy, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy,aryl, heterocyclyl, —OH, —OR₇, —CN, —NO₂, —NR₁R₇, —C(O)R₇, —C(O)NR₁R₇,—NR₁C(O)R₇, —SR₇, —S(O)R₇, —S(O)₂R₇, —OS(O)₂R₇, —S(O)₂NR₁R₇,—NR₁S(O)₂R₇, —(CR_(a)R_(b))_(m)NR₁R₇,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₇,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₇ or—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)COOR₈.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(23) where p is one and R₃ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(23) where p is one and R₃ is t-butyl.

In certain embodiments, the invention provides compounds of structuresI-R/S (24)-(25):

In certain embodiments, the invention provides compounds of structuresI-R/S (26)-(27):

In certain embodiments, the invention provides compounds of structureI-R/S(24)-(27) where each depicted alkyl is a straight chain or branchedalkyl, and in some embodiments is a C₁—C straight chain or branchedalkyl, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,isopropyl, iso-butyl, sec-butyl or t-butyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —OH.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)COOR₈.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —N(R₁)SO₂R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —NHCH₂COOH.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —NH(CHR_(b))COOH where R_(b) is alkyloptionally substituted with R₇, —(CHR₄₀)_(m)OR₄₀, —(CHR₄₀)_(m)SR₄₀,—(CHR₄₀)_(m)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)OR₄₀ or —(CHR₄₀)_(m)—S—S—R₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —NH(CR_(a)R_(b))_(m)COOH where R_(a) and R_(b)are independently H, alkyl optionally substituted with R₇,—(CHR₄₀)_(m)OR₄₀, —(CHR₄₀)_(m)SR₄₀, —(CHR₄₀)_(m)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)NR₄₁R₄₂, —(CHR₄₀))_(m)C(O)N(R₁)(CHR₄₀)_(m)—NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)—(CHR₄₀)_(m)C(O)NR₄₁R₄₂,—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)OR₄₀ or —(CHR₄₀)_(m)—S—S—R₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —NR₁(CHR_(b))_(m)COOH where R₁ and R_(b) takentogether form heterocyclyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —NR₁(CR_(a)R_(b))_(m)COOH where R₁ and one ofR_(b) taken together form heterocyclyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —NR₁(CR_(a)R_(b))_(m)COOH where any two R_(a)and R_(b) taken together with the carbon to which they are attached forma cycloalkyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —NH(CR_(a)R_(b))_(m)COOH where one of R_(a)and R_(b) is H and the other R_(a) and R_(b) is aryl substituted withR₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —NR₁(CR_(a)R_(b))_(m)COOH, m is 2, R₁ ishydrogen, each occurrence of R_(a) and R_(b) are hydrogen, and R₈ ishydrogen:

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —NR₁(CR_(a)R_(b))_(m)COOH, m is 1 and R₁,R_(b) and R₈ are hydrogen:

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —NR₁(CR_(a)R_(b))_(m)COOH, m is 2, a singleR_(a) (i.e., one of the two) is hydrogen, each occurrence of R_(b) ishydrogen, and R₈ is hydrogen:

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is alkyloptionally substituted with R₇, wherein alkyl includes straight andbranched alkyl groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl and tert-butyl, as well as cycloalkylgroups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is methyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is heterocycle orheterocyclylalkyl, either which may be optionally substituted with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is heterocycle,such as pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl,imidazolinyl, hexahydropyrimidinyl, diazepanyl, triazinyl, imidazolyl,pyrrolidinyl, furanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl,dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl,thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl,dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl, any of which maybe optionally substituted with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is aryl oraralkyl, either of which may be optionally substituted with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is aryl oraralkyl, such as phenyl or benzyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is aryl orheteroaryl substituted with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is phenyl orbenzyl substituted with hydroxyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is —CH(OH)C₆H₅.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CHR₄₀)_(m)C(O)OR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CH₂)_(m)C(O)OH.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CHR₄₀)_(m)OR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is —(CH₂)_(m)OH.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is —CH₂OH.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CHR₄₀)_(m)SR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CH₂)_(m)SR₄₀, where R₄₀ is H or alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CHR₄₀)_(m)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CH₂)_(m)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CHR₄₀)_(m)C(O)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CH₂)_(m)C(O)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is —CH₂C(O)NH₂ or—CH₂CH₂C(O)NH₂

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CH₂)_(m)C(O)N(R₁)(CH₂)_(m)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CHR₄)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CH₂)_(m)C(O)N(R₁)(CH₂)_(m)C(O)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CHR₄)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)OR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CH₂)_(m)C(O)N(R₁)(CH₂)_(m)C(O)OR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where R_(a) is—(CHR₄₀)_(m)—S—S—R₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where, within the R_(a)group, R₁, R₄₀, R₄₁ and R₄₂ are hydrogen.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where, within the R_(a)group, m is 1.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-b) or (R₂-c) where, within the R_(a)group, m is 2.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)COORS where m is 1, R₈is hydrogen, R_(b) is hydrogen and R₁ and R_(a) taken together with theatoms to which they are attached form a heterocyclyl optionallysubstituted (singly or multiply) with R₇:

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)COOR₈ where m is 2, R₈is hydrogen, R_(b) of the second (CR_(a)R_(b)) group is hydrogen and R₁and R_(a) of the second (CR_(a)R_(b)) group taken together with theatoms to which they are attached form a heterocyclyl optionallysubstituted (singly or multiply) with R₇:

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R2-d) or (R2-e) where R₁ and R_(a) takentogether with the atoms to which they are attached form azetidinyl,pyrrolindinyl or piperidinyl, each of which is optionally substituted(singly or multiply) with R₇. Representative compounds of thisembodiment include compounds of structure I-R/S(1)-(27) where R₂ is:

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is N(R₁)(R₄₂):

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-f) where R₄₁ and R₄₂ are independentlyR₄₀, —(CHR₄₀)_(n)—C(O)OR₄₀, —(CHR₄₀)_(n)—C(O)R₄₀, —(CH₂)N(R₁)(R₇), arylor heteroaryl, which aryl or heteroaryl is optionally substituted(singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-f) where R₄₁ is hydrogen and R₄₂ is alkyloptionally substituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-f) where R₄₁ is hydrogen and R₄₂ is—(CHR₄₀)_(n)C(O)OR₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-f) where R₄₁ is hydrogen and R₄₂ is—(CHR₄₀)_(n)C(O)R₄₀.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-f) where R₄₁ is hydrogen and R₄₂ is—(CH₂)_(n)N(R₁)(R₇).

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-f) where R₄₁ is hydrogen and R₄₂ is aryloptionally substituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-f) where R₄₁ is hydrogen and R₄₂ isheteroaryl optionally substituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-f) where R₄₁ and R₄₂ taken together withthe N atom to which they are attached form a 3- to 7-memberedheterocyclyl optionally substituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-f) where R₄₁ and R₄₂ taken together withthe N atom to which they are attached form pyrazinyl, pyrimidinyl,pyridazinyl, thiadiazolyl, oxadiazolyl, imidazolinyl,hexahydropyrimidinyl, diazepanyl, triazinyl, imidazolyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl or pyridinyl, any of whichmay be optionally substituted (singly or multiply) with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)CON(R₁)(R₄₀).

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is R₂ is —N(R₁)(CR_(a)R_(b))_(m)CON(R₁)(R₄₀)where m is 1, R_(b) is hydrogen and R₁ and R_(a) taken together with theatoms to which they are attached form a heterocyclyl optionallysubstituted (singly or multiply) with R₇:

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is R₂ is —N(R₁)(CR_(a)R_(b))_(m)CON(R₁)(R₄₀)where m is 2, R_(b) of the second (CR_(a)R_(b)) group is hydrogen and R₁and R_(a) of the second (CR_(a)R_(b)) group taken together with theatoms to which they are attached form a heterocyclyl optionallysubstituted (singly or multiply) with R₇:

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is (R₂-h) where R₁ and R_(a) taken together withthe atoms to which they are attached form azetidinyl, pyrrolindinyl,piperidinyl optionally substituted (singly or multiply) with R₇.Representative compounds of this embodiment include compounds ofstructure I-R/S(1)-(27) where R₂ is:

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)N(R₁)C(O)O(R₈).

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)N(R₁)(R₇).

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)CON(R₁)heterocyclyl.

In certain embodiments, the invention provides compounds of structureI-R/S(1)-(27) where R₂ is —N(R₁)(CR_(a)R_(b))_(m)-heterocyclyl, whichheterocyclyl may be optionally substituted with R₇.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention together with atleast one pharmaceutically acceptable carrier, diluent or excipient.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention and a secondmedicament. In certain of such embodiments, the second medicament is aGLP-1 agonist or a DPPIV inhibitor.

In certain embodiments, the invention provides a method of use ofcompounds of the invention for preparation of a medicament.

In certain embodiments, the invention provides a pharmaceuticalcombination comprising a compound of the invention and a secondmedicament. In various such embodiments, the second medicament is anagonist or modulator for glucagon receptor, GIP receptor, GLP-2receptor, or PTH receptor, or glucagon-like peptide 1 (GLP-1) receptor.In various such embodiments, the second medicament is exenatide,liraglutide, taspoglutide, albiglutide, or lixisenatide or other insulinregulating peptide. In various such embodiments, the second medicamentis a DPPIV inhibitor, such as sitagliptin. In various such embodiments,the second medicament is medically indicated for the treatment of typeII diabetes. In various combinations, the second medicament is asodium-glucose co-transporter (SGLT) inhibitor, such as a SGLT1 and/orSGLT2 inhibitor, including dapagliflozin, empagliflozin andcanagliflozin. In various such embodiments, the second medicament is abiguanide such as metformin, a sulfonylurea such as glibenclamide,glipizide, gliclazide, and glimepiride, a meglitinide such asrepaglinide and mateglinide, a thiazolidinedione such as pioglitazoneand rosiglitazone, an α-glucosidase inhibitor such as acarbose andmiglitol, a bile acid sequestrant such as colesevelam, and/or adopamine-2 agonist such as bromocriptine.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention and a secondmedicament, wherein the second medicament is metformin.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention and a secondmedicament, wherein the second medicament is sitagliptin.

In certain embodiments, a method is provided for activation,potentiation or agonism of a glucagon-like peptide 1 comprisingcontacting the receptor with an effective amount of a compound,pharmaceutical composition or pharmaceutical combination of theinvention.

In further embodiments, a method is provided for activation or agonismof a GLP-1 receptor by contacting the receptor with an effective amountof an invention compound and GLP-1 peptides GLP-1(9-36) and GLP-1(7-36),pharmaceutical composition or pharmaceutical combination, wherein theGLP-1 receptor is disposed within a living mammal; in certainembodiments wherein such mammal is a human.

In certain embodiments, a method is provided for treatment of amalcondition in a subject for which activation, potentiation or agonismof a GLP-1 receptor is medically indicated, by administering aneffective amount of an invention compound to the subject at a frequencyand for a duration of time sufficient to provide a beneficial effect tothe patient. In yet further embodiments, a method is provided fortreatment of a malcondition in a patient for which activation,potentiation, or agonism of a GLP-1 receptor is medically indicated, byadministering an effective amount of an invention compound to thepatient at a frequency and for a duration of time sufficient to providea beneficial effect to the patient, wherein the malcondition comprisestype I diabetes, type II diabetes, gestational diabetes, obesity,excessive appetite, insufficient satiety, or metabolic disorder. Incertain embodiments, the subject is a patient or a human being. Incertain embodiments, the human being is afflicted with, or at risk ofdeveloping, a disease or condition selected from the group consisting oftype I diabetes, type II diabetes, gestational diabetes, obesity,excessive appetite, insufficient satiety, and metabolic disorder. Incertain of such embodiments, said disease is type I diabetes or type IIdiabetes.

In certain embodiments, the invention provides methods for synthesis ofcertain compounds including compounds of the invention as more fullyillustrated herein. In certain other embodiments, the invention providescertain intermediate compounds associated with such methods of synthesisas illustrated herein.

In certain embodiments, methods are provided for use of an inventioncompound for preparation of a medicament adapted for treatment of adisorder or a malcondition wherein activation or inhibition of a GLP-1receptor is medically indicated. In certain embodiments, themalcondition comprises type I diabetes, type II diabetes, gestationaldiabetes, obesity, excessive appetite, insufficient satiety, andmetabolic disorder. Preferably said disease is type I diabetes or typeII diabetes.

In certain embodiments, the method additionally comprises administeringto the subject a second medicament selected from the group ofbiguanides, peptidic GLP-1 agonists and DPPIV inhibitors, wherein suchsecond medicament is either a component of the pharmaceuticalcomposition or a second pharmaceutical composition. In certain of suchembodiments, the second medicament can be metformin, exenatide orsitagliptin.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

The terms “comprising,” “including,” “having,” “composed of,” areopen-ended terms as used herein, and do not preclude the existence ofadditional elements or components. In a claim element, use of the forms“comprising,” “including,” “having,” or “composed of” means thatwhatever element is comprised, had, included, or composes is notnecessarily the only element encompassed by the subject of the clausethat contains that word.

As used herein, “individual” (as in the subject of the treatment) meansboth mammals and non-mammals. Mammals include, for example, humans;non-human primates, e.g., apes and monkeys; cattle; horses; sheep; andgoats. Non-mammals include, for example, fish and birds.

A “receptor”, as is well known in the art, is a biomolecular entityusually comprising a protein that specifically binds a structural classof ligands or a single native ligand in a living organism, the bindingof which causes the receptor to transduce the binding signal intoanother kind of biological action, such as signaling a cell that abinding event has occurred, which causes the cell to alter its functionin some manner. An example of transduction is receptor binding of aligand causing alteration of the activity of a “G-protein” in thecytoplasm of a living cell. Any molecule, naturally occurring or not,that binds to a receptor and activates it for signal transduction, isreferred to as an “agonist” or “activator.” Any molecule, naturallyoccurring or not, that binds to a receptor, but does not cause signaltransduction to occur, and which can block the binding of an agonist andits consequent signal transduction, is referred to as an “antagonist.”Certain molecules bind to receptors at locations other than the bindingsites of their natural ligands and such allosteric binding molecules maypotentiate, activate or agonize the receptor and may enhance the effectof a natural ligand or a co-administered ligand.

A “GLP-1 compound” or “GLP-1 agonist” or “GLP-1 activator” or “GLP-1inhibitor” or “GLP-1 antagonist” or “GLP-1 potentiator” or “GLP-1modulator” as the terms are used herein refer to compounds that interactin some way with the GLP-1 receptor. They can be agonists, potentiators,or activators, or they can be antagonists or inhibitors. A “GLP-1compound” of the invention can be selective for action of the GLP-1receptor family.

“Substantially” as the term is used herein means completely or almostcompletely; for example, a composition that is “substantially free” of acomponent either has none of the component or contains such a traceamount that any relevant functional property of the composition isunaffected by the presence of the trace amount, or a compound is“substantially pure” is there are only negligible traces of impuritiespresent.

“Substantially enantiomerically or diasteromerically” pure means a levelof enantiomeric or diasteromeric enrichment of one enantiomer withrespect to the other enantiomer or diasteromer of at least about 80%,and more preferably in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or99.9%.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder.

The expression “effective amount”, when used to describe use of acompound of the invention in providing therapy to a patient sufferingfrom a disorder or malcondition mediated by GLP-1 refers to the amountof a compound of the invention that is effective to bind to as anagonist or as an antagonist a GLP-1 receptor in the individual'stissues, wherein the GLP-1 is implicated in the disorder, wherein suchbinding occurs to an extent sufficient to produce a beneficialtherapeutic effect on the patient. Similarly, as used herein, an“effective amount” or a “therapeutically effective amount” of a compoundof the invention refers to an amount of the compound that alleviates, inwhole or in part, symptoms associated with the disorder or condition, orhalts or slows further progression or worsening of those symptoms, orprevents or provides prophylaxis for the disorder or condition. Inparticular, a “therapeutically effective amount” refers to an amounteffective, at dosages and for periods of time necessary, to achieve thedesired therapeutic result by acting as an agonist of GLP-1 activity. Atherapeutically effective amount is also one in which any toxic ordetrimental effects of compounds of the invention are outweighed by thetherapeutically beneficial effects. For example, in the context oftreating a malcondition mediated by activation of a GLP-1 receptor, atherapeutically effective amount of a GLP-1 receptor agonist of theinvention is an amount sufficient to control the malcondition, tomitigate the progress of the malcondition, or to relieve the symptoms ofthe malcondition. Examples of malconditions that can be so treatedinclude, but not limited to, type II diabetes.

All chiral, diastereomeric, racemic forms of a structure are intended,unless a particular stereochemistry or isomeric form is specificallyindicated. Compounds used in the present invention can include enrichedor resolved optical isomers at any or all asymmetric atoms as areapparent from the depictions, at any degree of enrichment. Both racemicand diastereomeric mixtures, as well as the individual optical isomerscan be synthesized so as to be substantially free of their enantiomericor diastereomeric partners, and these are all within the scope ofcertain embodiments of the invention.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.Once the priority ranking of the four groups is determined, the moleculeis oriented so that the lowest ranking group is pointed away from theviewer. Then, if the descending rank order of the other groups proceedsclockwise, the molecule is designated (R) and if the descending rank ofthe other groups proceeds counterclockwise, the molecule is designated(S). In the example in Scheme 14, the Cahn-Ingold-Prelog ranking isA>B>C>D. The lowest ranking atom, D is oriented away from the viewer.

“Isolated optical isomer” means a compound which has been substantiallypurified from the corresponding optical isomer(s) of the same formula.Preferably, the isolated isomer is at least about 80%, and preferably atleast 80% or even at least 85% pure. In other embodiments, the isolatedisomer is at least 90% pure or at least 98% pure, or at least about 99%pure, by weight.

Enantiomers are sometimes called optical isomers because a pureenantiomer rotates plane-polarized light in a particular direction. Ifthe light rotates clockwise, then that enantiomer is labeled “(+)” or“d” for dextrorotatory, its counterpart will rotate the lightcounterclockwise and is labeled “(−)” or “l” for levorotatory.

The terms “racemate” and “racemic mixture” are frequently usedinterchangeably. A racemate is an equal mixture of two enantiomers. Aracemate is labeled “(±)” because it is not optically active (i.e., willnot rotate plane-polarized light in either direction since itsconstituent enantiomers cancel each other out).

It is understood that due to chemical properties (i.e., resonancelending some double bond character to the C—N bond) of restrictedrotation about the amide bond linkage (as illustrated below) it ispossible to observe separate rotamer species and even, under somecircumstances, to isolate such species, example shown below. It isfurther understood that certain structural elements, including stericbulk or substituents on the amide nitrogen, may enhance the stability ofa rotamer to the extent that a compound may be isolated as, and existindefinitely, as a single stable rotamer. The present inventiontherefore includes any possible stable rotamers of compounds of theinvention which are biologically active in the treatment of type Idiabetes, type II diabetes, gestational diabetes, obesity, excessiveappetite, insufficient satiety, or metabolic disorder.

All structures encompassed within a claim are “chemically feasible”, bywhich is meant that the structure depicted by any combination orsubcombination of optional substituents meant to be recited by the claimis physically capable of existence with at least some stability as canbe determined by the laws of structural chemistry and byexperimentation. Structures that are not chemically feasible are notwithin a claimed set of compounds. Further, isotopes of the atomsdepicted (such as deuterium and tritium in the case of hydrogen) areencompassed within the scope of this invention. For example, it shouldbe understood that depiction herein of compounds having one or morehydrogen atoms is intended to encompass compounds having such hydrogenatoms replaced with deuterium (or tritium) at one or more locations.Such “deuterated compounds”, whether partial (i.e., less than all thehydrogen atoms replaced with deuterium) or complete (i.e., all hydrogenatoms replaced with deuterium) are within the scope of the compounds ofthis invention.

In general, “substituted” refers to an organic group as defined hereinin which one or more bonds to a hydrogen atom contained therein arereplaced by one or more bonds to a non-hydrogen atom such as, but notlimited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxygroups, oxo(carbonyl) groups, carboxyl groups including carboxylicacids, carboxylates, and carboxylate esters; a sulfur atom in groupssuch as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups,sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atomin groups such as amines, hydroxylamines, nitriles, nitro groups,N-oxides, hydrazides, azides, and enamines; and other heteroatoms invarious other groups. Non-limiting examples of substituents that can bebonded to a substituted carbon (or other) atom include F, Cl, Br, I,OR′, OC(O)N(R′)₂, CN, CF₃, OCF₃, R′, O, S, C(O), S(O), methylenedioxy,ethylenedioxy, N(R′)₂, SR′, SOR′, SO₂R′, SO₂N(R′)₂, SO₃R′, C(O)R′,C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, C(O)N(R′)₂,OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂NHC(O)R′, (CH₂)O₂N(R′)N(R′)₂,N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′,N(R′)SO₂N(R′)₂, N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′)₂,N(R′)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, orC(═NOR′)R′ wherein R′ can be hydrogen or a carbon-based moiety, andwherein the carbon-based moiety can itself be further substituted.

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groupsas well as other substituted groups also include groups in which one ormore bonds to a hydrogen atom are replaced by one or more bonds,including double or triple bonds, to a carbon atom, or to a heteroatomsuch as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester,amide, imide, urethane, and urea groups; and nitrogen in imines,hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups include substituted aryl, heterocyclyl andheteroaryl groups. Substituted ring groups can be substituted by one ormore substituents at any available ring position. In some embodiments,two substituents on a substituted ring group may taken together with thering to which they are attached to form a ring, such that the two ringsare fused together. For example, benzodioxolyl is a fused ring systemformed by two substituents taken together on a phenyl group.

Such substituted ring groups also include rings and fused ring systemsin which a bond to a hydrogen atom is replaced with a bond to a carbonatom. Therefore, substituted aryl, heterocyclyl and heteroaryl groupscan also be substituted with alkyl, alkenyl, cycloalkyl, aryl,heteroaryl, and alkynyl groups as defined herein, which can themselvesbe further substituted.

The term “heteroatoms” as used herein refers to non-carbon andnon-hydrogen atoms, capable of forming covalent bonds with carbon, andis not otherwise limited. Typical heteroatoms are N, O, and S. Whensulfur (S) is referred to, it is understood that the sulfur can be inany of the oxidation states in which it is found, thus includingsulfoxides (R—S(O)—R′) and sulfones (R—S(O)₂—R′), unless the oxidationstate is specified; thus, the term “sulfone” encompasses only thesulfone form of sulfur; the term “sulfide” encompasses only the sulfide(R—S—R′) form of sulfur. When the phrases such as “heteroatoms selectedfrom the group consisting of O, NH, NR′ and S,” or “[variable] is O, S .. . ” are used, they are understood to encompass all of the sulfide,sulfoxide and sulfone oxidation states of sulfur.

“Alkyl” groups include straight chain and branched alkyl groups andcycloalkyl groups having from 1 to about 20 carbon atoms, and typicallyfrom 1 to 12 carbons (C₁-C₁₂ alkyl), or, in some embodiments, from 1 to8 carbon atoms (C₁-C₅ alkyl), or, in some embodiments, from 1 to 4carbon atoms (C₁-C₄ alkyl). In the case of cycloalkyl groups, suchgroups have from 3-20 carbon atoms. Examples of straight chain alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples ofbranched alkyl groups include, but are not limited to, isopropyl,iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and2,2-dimethylpropyl groups. Alkyl groups as used herein may optionallyinclude one or more further substituent groups. Representativesubstituted alkyl groups can be substituted one or more times with anyof the groups listed above, for example, amino, hydroxy, cyano, carboxy,nitro, thio, alkoxy, and halogen groups.

“Alkenyl” groups include straight and branched chain and cyclic alkylgroups as defined above, except that at least one double bond existsbetween two carbon atoms. Thus, alkenyl groups have from 2 to about 20carbon atoms, and typically from 2 to 12 carbons or, in someembodiments, from 2 to 8 carbon atoms. Examples include, but are notlimited to —CH═CH₂, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, —CH═CHCH₂CH₃, —CH═CH(CH₂)₂CH₃,—CH═CH(CH₂)₃CH₃, —CH═CH(CH₂)₄CH₃, vinyl, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

“Alkynyl” groups include straight and branched chain alkyl groups,except that at least one triple bond exists between two carbon atoms.Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typicallyfrom 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.Examples include, but are not limited to —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃),—CH₂C≡CH, —CH₂C≡C(CH₃), and —CH₂C≡C(CH₂CH₃), among others.

“Cycloalkyl” groups are alkyl groups forming a ring structure, which canbe substituted or unsubstituted, wherein the ring is either completelysaturated, partially unsaturated, or fully unsaturated, wherein if thereis unsaturation, the conjugation of the pi-electrons in the ring do notgive rise to aromaticity. Examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkylgroup has 3 to 8 ring members, whereas in other embodiments the numberof ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkylgroups further include polycyclic cycloalkyl groups such as, but notlimited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, andcarenyl groups, and fused rings such as, but not limited to, decalinyl,and the like. Cycloalkyl groups also include rings that are substitutedwith straight or branched chain alkyl groups as defined above.Representative substituted cycloalkyl groups can be mono-substituted orsubstituted one or more times with any of the groups listed above, forexample, but not limited to, amino, hydroxy, cyano, carboxy, nitro,thio, alkoxy, and halogen groups.

“(Cycloalkyl)alkyl” groups, also referred to as “cycloalkylalkyl”, arealkyl groups as defined above in which a hydrogen or carbon bond of thealkyl group is replaced with a bond to a cycloalkyl group as definedabove.

The term “cycloalkenyl” alone or in combination denotes a cyclic alkenylgroup wherein at least one double bond is present in the ring structure.Cycloalkenyl groups include cycloalkyl groups having at least one doublebond between two adjacent carbon atoms. Thus for example, cycloalkenylgroups include but are not limited to cyclohexenyl, cyclopentenyl, andcyclohexadienyl groups, as well as polycyclic and/or bridging ringsystems such as adamantine.

“(Cycloalkenyl)alkyl” groups, also referred to as “cycloalkylalkyl”, arealkyl groups as defined above in which a hydrogen or carbon bond of thealkyl group is replaced with a bond to a cycloalkenyl group as definedabove.

The terms “carbocyclic” and “carbocyclyl” denote a ring structurewherein the atoms of the ring are carbon. In some embodiments, thecarbocyclyl has 3 to 8 ring members, whereas in other embodiments thenumber of ring carbon atoms is 4, 5, 6, or 7. Carbocyclyl includes, forexample, cycloalkyl and cycloalkenyl. Unless specifically indicated tothe contrary, the carbocyclic ring can be substituted with as many as Nsubstituents wherein N is the size of the carbocyclic ring with forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkyl, alkoxy, andhalogen groups.

“(Carbocyclyl)alkyl” groups, also referred to as “carbocyclylalkyls”,are alkyl groups as defined above in which a hydrogen or carbon bond ofthe alkyl group is replaced with a bond to a carbocyclyl as definedabove.

A “nonaromatic carbocyclyl” or a “nonaromatic carbocyclylalkyl” is agroup in which the carbocyclic ring of the carbocyclyl orcarbocyclylalkyl is a completely saturated, a partially unsaturated, ora fully unsaturated carbocyclyl, wherein if there is unsaturation, theconjugation of the pi-electrons of the carbocyclic ring do not give riseto aromaticity.

“Aryl” groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Thus aryl groups include, but are not limited to, phenyl,azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl,triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl,anthracenyl, and naphthyl groups. In some embodiments, aryl groupscontain 6-14 carbons in the ring portions of the groups. The phrase“aryl groups” includes groups containing fused rings, such as fusedaromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, andthe like), and also includes substituted aryl groups that have othergroups, including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, or alkoxy groups, bonded to one of the ring atoms.Representative substituted aryl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-,or 6-substituted phenyl or naphthyl groups, which can be substitutedwith groups including but not limited to those listed above.

“Aralkyl” groups are alkyl, alkenyl or alkynyl groups as defined abovein which a hydrogen atom of an alkyl, alkenyl or alkynyl group isreplaced with an aryl group as defined above. Representative aralkylgroups include benzyl (—CH₂phenyl), phenylethyl (—CH₂CH₂phenyl) andphenylethylene (—CH═CHphenyl) groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl. The aryl moiety or the alkyl, alkenyl oralkynyl moiety or both are optionally substituted with other groups,including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, or alkoxy groups.

“Heterocyclyl” or “heterocyclic” groups include aromatic andnon-aromatic ring moieties containing 3 or more ring members, of whichone or more is a heteroatom such as, but not limited to, N, O, S, or P.In some embodiments, heterocyclyl groups include 3 to 20 ring members,whereas other such groups have 3 to 15 ring members, including forexample single ring systems containing 5, 6 or 7 ring members. At leastone ring contains a heteroatom, but every ring in a polycyclic systemneed not contain a heteroatom. For example, a dioxolanyl ring and abenzdioxolanyl ring system (methylenedioxyphenyl ring system) are bothheterocyclyl groups within the meaning herein. A heterocyclyl groupdesignated as a C₂-heterocyclyl can be a 5-ring with two carbon atomsand three heteroatoms, a 6-ring with two carbon atoms and fourheteroatoms, and so forth. Likewise a C₄-heterocyclyl can be a 5-ringwith one heteroatom, a 6-ring with two heteroatoms, and so forth. Thenumber of carbon atoms plus the number of heteroatoms sums up to equalthe total number of ring atoms.

The term “heterocyclyl” includes fused ring species including thosehaving fused aromatic and non-aromatic groups. The phrase also includespolycyclic and/or bridging ring systems containing a heteroatom such as,but not limited to, quinuclidyl and 7-azabicyclo[2.2.1]heptane, and alsoincludes heterocyclyl groups that have substituents, including but notlimited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, oralkoxy groups, bonded to one of the ring members. A heterocyclyl groupas defined herein can be a heteroaryl group or a partially or completelysaturated cyclic group including at least one ring heteroatom.Heterocyclyl groups include, but are not limited to, pyrazinyl,pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl, imidazolinyl,hexahydropyrimidinyl, diazepanyl, triazinyl, imidazolyl, pyrrolidinyl,furanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl,piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl,benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl,dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.Heterocyclyl groups can be substituted. Representative substitutedheterocyclyl groups can be mono-substituted or substituted more thanonce, including but not limited to, rings containing at least oneheteroatom which are mono, di, tri, tetra, penta, hexa, orhigher-substituted with substituents such as those listed above,including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, and alkoxy groups, and in the case of twosubstituents on the same carbon atom of the heterocycle include oxo (═O)and thioxo (═S).

“Heteroaryl” groups are aromatic ring moieties containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. A heteroaryl group designated as a C₂-heteroaryl can bea 5-ring with two carbon atoms and three heteroatoms, a 6-ring with twocarbon atoms and four heteroatoms and so forth. Likewise a C₄-heteroarylcan be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, andso forth. The number of carbon atoms plus the number of heteroatoms sumsup to equal the total number of ring atoms. Heteroaryl groups include,but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl,pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thiadiazolyl,imidazolyl, oxadiazolyl, thienyl, triazolyl, tetrazolyl, triazinyl,thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl,benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, andquinazolinyl groups. The terms “heteroaryl” and “heteroaryl groups”include fused ring compounds such as wherein at least one ring, but notnecessarily all rings, are aromatic, including tetrahydroquinolinyl,tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl. The term alsoincludes heteroaryl groups that have other groups bonded to one of thering members, including but not limited to alkyl, halo, amino, hydroxy,cyano, carboxy, nitro, thio, or alkoxy groups. Representativesubstituted heteroaryl groups can be substituted one or more times withgroups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl(1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl(1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), isoxazolyl, quinazolinyl,fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl,pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl(1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), pyrazolo[1,5-a]pyridinyl, quinolyl(2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl,8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl),benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl,4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl,7-benzo[b]furanyl), isobenzofuranyl, 2,3-dihydro-benzo[b]furanyl(2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl),4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl),benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl,4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl,7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl,(2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl),4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl),6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl),indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl,6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl,5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl(1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl,6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl(1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl,2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,7-benzothiazolyl), benzo[d]isoxazolyl, carbazolyl (1-carbazolyl,2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine(5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl,5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl,5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl, alkenyl or alkynyl groups as definedabove in which a hydrogen or carbon bond of an alkyl, alkenyl or alkynylgroup is replaced with a bond to a heterocyclyl group as defined above.Representative heterocyclyl alkyl groups include, but are not limitedto, furan-2-yl methyl, furan-3-yl methyl, pyridine-2-yl methyl(α-picolyl), pyridine-3-yl methyl (β-picolyl), pyridine-4-yl methyl(γ-picolyl), tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.Heterocyclylalkyl groups can be substituted on the heterocyclyl moiety,the alkyl, alkenyl or alkynyl moiety, or both.

“Heteroarylalkyl” groups are alkyl, alkenyl or alkynyl groups as definedabove in which a hydrogen or carbon bond of an alkyl, alkenyl or alkynylgroup is replaced with a bond to a heteroaryl group as defined above.Heteroarylalkyl groups can be substituted on the heteroaryl moiety, thealkyl, alkenyl or alkynyl moiety, or both.

By a “ring system” as the term is used herein is meant a moietycomprising one, two, three or more rings, which can be substituted withnon-ring groups or with other ring systems, or both, which can be fullysaturated, partially unsaturated, fully unsaturated, or aromatic, andwhen the ring system includes more than a single ring, the rings can befused, bridging, or spirocyclic. By “spirocyclic” is meant the class ofstructures wherein two rings are fused at a single tetrahedral carbonatom, as is well known in the art.

A “monocyclic, bicyclic or polycyclic, aromatic or partially aromaticring” as the term is used herein refers to a ring system including anunsaturated ring possessing 4n+2 pi electrons, or a partially reduced(hydrogenated) form thereof. The aromatic or partially aromatic ring caninclude additional fused, bridged, or spiro rings that are notthemselves aromatic or partially aromatic. For example, naphthalene andtetrahydronaphthalene are both a “monocyclic, bicyclic or polycyclic,aromatic or partially aromatic ring” within the meaning herein. Also,for example, a benzo-[2.2.2]-bicyclooctane is also a “monocyclic,bicyclic or polycyclic, aromatic or partially aromatic ring” within themeaning herein, containing a phenyl ring fused to a bridged bicyclicsystem. A fully saturated ring has no double bonds therein, and iscarbocyclic or heterocyclic depending on the presence of heteroatomswithin the meaning herein.

When two “R” groups are said to be joined together or taken together toform a ring, it is meant that together with the carbon atom or anon-carbon atom (e.g., nitrogen atom), to which they are bonded, theymay form a ring system. In general, they are bonded to one another toform a 3- to 7-membered ring, or a 5- to 7-membered ring. Non-limitingspecific examples are the cyclopentyl, cyclohexyl, cycloheptyl,piperidinyl, piperazinyl, pyrolidinyl, pyrrolyl, pyridinyl.

The term “alkoxy” refers to an oxygen atom connected to an alkyl group,including a cycloalkyl group, as are defined above. Examples of linearalkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy,n-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy n-nonyloxy,and the like. Examples of branched alkoxy include but are not limited toisopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and thelike. Examples of cyclic alkoxy include but are not limited tocyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moiety. Examples include but are not limited tophenoxy, naphthyloxy, and benzyloxy.

An “acyl” group as the term is used herein refers to a group containinga carbonyl moiety wherein the group is bonded via the carbonyl carbonatom. The carbonyl carbon atom is also bonded to another carbon atom,which can be part of an alkyl, aryl, aralkyl cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl group or the like. In the special case wherein thecarbonyl carbon atom is bonded to a hydrogen, the group is a “formyl”group, an acyl group as the term is defined herein. An acyl group caninclude 0 to about 12-20 additional carbon atoms bonded to the carbonylgroup. An acyl group can include double or triple bonds within themeaning herein. An acryloyl group is an example of an acyl group. Anacyl group can also include heteroatoms within the meaning here. Anicotinoyl group (pyridyl-3-carbonyl) group is an example of an acylgroup within the meaning herein. Other examples include acetyl, benzoyl,phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and thelike. When the group containing the carbon atom that is bonded to thecarbonyl carbon atom contains a halogen, the group is termed a“haloacyl” group. An example is a trifluoroacetyl group.

The term “amine” includes primary, secondary, and tertiary amineshaving, e.g., the formula N(group)₃ wherein each group can independentlybe H or non-H, such as alkyl, aryl, and the like. Amines include but arenot limited to R—NH₂, for example, alkylamines, arylamines,alkylarylamines; R₂NH wherein each R is independently selected, such asdialkylamines, diarylamines, aralkylamines, heterocyclylamines and thelike; and R₃N wherein each R is independently selected, such astrialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, andthe like. The term “amine” also includes ammonium ions as used herein.

An “amino” group is a substituent of the form —NH₂, —NHR, —NR₂, —NR₃ ⁺,wherein each R is independently selected, and protonated forms of each.Accordingly, any compound substituted with an amino group can be viewedas an amine.

An “ammonium” ion includes the unsubstituted ammonium ion NH₄ ⁺, butunless otherwise specified, it also includes any protonated orquaternarized forms of amines. Thus, trimethylammonium hydrochloride andtetramethylammonium chloride are both ammonium ions, and amines, withinthe meaning herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR₂, and —NRC(O)R groups, respectively. Amide groups thereforeinclude but are not limited to carbamoyl groups (—C(O)NH₂) and formamidegroups (—NHC(O)H). A “carboxamido” group is a group of the formulaC(O)NR₂, wherein R can be H, alkyl, aryl, etc.

The term “carbonyl,” refers to a —C(O)— group.

“Halo,” “halogen,” and “halide” include fluorine, chlorine, bromine andiodine.

The term “perhaloalkyl” refers to an alkyl group where all of thehydrogen atoms are replaced by halogen atoms. Perhaloalkyl groupsinclude, but are not limited to, —CF₃ and —C(CF₃)₃. The term “haloalkyl”refers to an alkyl group where some but not necessarily all of thehydrogen atoms are replaced by halogen atoms. Haloalkyl groups includebut are not limited to —CHF₂ and —CH₂F.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms. Perhaloalkoxy groupsinclude, but are not limited to, —OCF₃ and —OC(CF₃)₃. The term“haloalkoxy” refers to an alkoxy group where some but not necessarilyall of the hydrogen atoms are replaced by halogen atoms. Haloalkoxygroups include but are not limited to —OCHF₂ and —OCH₂F.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compounds of thepresent invention may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds of theinvention. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility inprocess of synthesis, purification or formulation of compounds of theinvention.

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic acetic, propionic, succinic, glycolic, gluconic,lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic,2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Examples of pharmaceuticallyunacceptable acid addition salts include, for example, perchlorates andtetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. Although pharmaceutically unacceptable salts are notgenerally useful as medicaments, such salts may be useful, for exampleas intermediates in the synthesis of Formula I compounds, for example intheir purification by recrystallization. All of these salts may beprepared by conventional means from the corresponding compound accordingto Formula I by reacting, for example, the appropriate acid or base withthe compound according to Formula I. The term “pharmaceuticallyacceptable salts” refers to nontoxic inorganic or organic acid and/orbase addition salts, see, for example, Lit et al., Salt Selection forBasic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated byreference herein.

A “hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometricquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form, i.e., a compound in water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “solvate” is a similar composition except that a solvent other thatwater replaces the water. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometric or non-stoichiometric.As the term is used herein a “solvate” refers to a solid form, i.e., acompound in solution in a solvent, while it may be solvated, is not asolvate as the term is used herein.

A “prodrug” as is well known in the art is a substance that can beadministered to a patient where the substance is converted in vivo bythe action of biochemicals within the patient's body, such as enzymes,to the active pharmaceutical ingredient. Examples of prodrugs includeesters of carboxylic acid groups, which can be hydrolyzed by endogenousesterases as are found in the bloodstream of humans and other mammals.

“Isotopes” are well known in the art and refer to atoms with the samenumber of protons but different number of neutrons. For example, carbon12, the most common form of carbon, has six protons and six neutrons,whereas carbon 14 has six protons and eight neutrons.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described. Moreover, where features or aspects ofthe invention are described in terms of Markush groups, those skilled inthe art will recognize that the invention is also thereby described interms of any combination of individual members or subgroups of membersof Markush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

The GLP-1 compounds, their pharmaceutically acceptable salts orhydrolyzable esters of the present invention may be combined with apharmaceutically acceptable carrier to provide pharmaceuticalcompositions useful for treating the biological conditions or disordersnoted herein in mammalian species, and more preferably, in humans. Theparticular carrier employed in these pharmaceutical compositions mayvary depending upon the type of administration desired (e.g.,intravenous, oral, topical, suppository, or parenteral).

In preparing the compositions in oral liquid dosage forms (e.g.,suspensions, elixirs and solutions), typical pharmaceutical media, suchas water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like can be employed. Similarly, when preparingoral solid dosage forms (e.g., powders, tablets and capsules), carrierssuch as starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like can be employed.

Another aspect of an embodiment of the invention provides compositionsof the compounds of the invention, alone or in combination with anotherGLP-lagonist or another type of therapeutic agent or second medicament,or both. Non-limiting examples of the GLP-1 receptor agonists includeexenatide, liraglutide, taspoglutide, albiglutide, lixisenatide, andmixtures thereof.

In one embodiment, the GLP-lagonist is exenatide (Byetta®) or ByettaLAR®. Exenatide is described, for example, in U.S. Pat. Nos. 5,424,286;6,902,744; 7,297,761, and others, the contents of each of which isherein incorporated by reference in its entirety.

In one embodiment, the GLP-lagonist is liraglutide (VICTOZA®) (alsocalled NN-2211 and [Arg34,Lys26]-(N-epsilon-(gamma-Glu(N-alpha-hexadecanoyl))-GLP-1 (7-37)),includes the sequence HAEGTFTSDVSSYLEGQAAKEFIAWKVRGRG and is availablefrom Novo Nordisk (Denmark) or Scios (Fremont, Calif. USA). See, e.g.,Elbrond et al., 2002, Diabetes Care. August; 25(8):1398404; Agerso etal., 2002, Diabetologia. February; 45(2):195-202).

In one embodiment, the GLP-lagonist is taspoglutide (CAS Registry No.275371-94-3) and is available from Hoffman La-Roche. See, for example,U.S. Pat. No. 7,368,427, the contents of which are herein incorporatedby reference in its entirety.

In one embodiment, the GLP-1 agonist isalbiglutide (SYNCRIA® fromGlaxoSmithKline).

In another embodiment, the GLP-1 agonist is lixisenatide (Lyxumia® fromSanofi-Aventis/Zealand Pharma).

Non-limiting examples of the second medicaments are as disclosed above.In various such embodiments, the second medicament is exenatide,liraglutide, taspoglutide, albiglutide, or lixisenatide or other insulinregulating peptide. In various such embodiments, the second medicamentis a DPPIV inhibitor. In various such embodiments, the second medicamentis medically indicated for the treatment of type II diabetes. In varioussuch embodiments, the second medicament is a biguanide, a sulfonylurea,a meglitinide, a thiazolidinedione, an α-glucosidase inhibitor, a bileacid sequestrant, and/or a dopamine-2 agonist.

In another embodiment, the second medicament is metformin.

In another embodiment, the second medicament is sitagliptin.

As set forth herein, compounds of the invention include stereoisomers,tautomers, solvates, hydrates, salts including pharmaceuticallyacceptable salts, and mixtures thereof. Compositions containing acompound of the invention can be prepared by conventional techniques,e.g., as described in Remington: The Science and Practice of Pharmacy,19th Ed., 1995, incorporated by reference herein. The compositions canappear in conventional forms, for example capsules, tablets, aerosols,solutions, suspensions or topical applications.

Typical compositions include a compound of the invention and apharmaceutically acceptable excipient which can be a carrier or adiluent. For example, the active compound will usually be mixed with acarrier, or diluted by a carrier, or enclosed within a carrier which canbe in the form of an ampoule, capsule, sachet, paper, or othercontainer. When the active compound is mixed with a carrier, or when thecarrier serves as a diluent, it can be solid, semi-solid, or liquidmaterial that acts as a vehicle, excipient, or medium for the activecompound. The active compound can be adsorbed on a granular solidcarrier, for example contained in a sachet. Some examples of suitablecarriers are water, salt solutions, alcohols, polyethylene glycols,polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent can include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax.

The formulations can be mixed with auxiliary agents which do notdeleteriously react with the active compounds. Such additives caninclude wetting agents, emulsifying and suspending agents, salt forinfluencing osmotic pressure, buffers and/or coloring substancespreserving agents, sweetening agents or flavoring agents. Thecompositions can also be sterilized if desired.

The route of administration can be any route which effectivelytransports the active compound of the invention to the appropriate ordesired site of action, such as oral, nasal, pulmonary, buccal,subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot,subcutaneous, intravenous, intraurethral, intramuscular, intranasal,ophthalmic solution or an ointment, the oral route being preferred.

For parenteral administration, the carrier will typically comprisesterile water, although other ingredients that aid solubility or serveas preservatives can also be included. Furthermore, injectablesuspensions can also be prepared, in which case appropriate liquidcarriers, suspending agents and the like can be employed.

For topical administration, the compounds of the present invention canbe formulated using bland, moisturizing bases such as ointments orcreams.

If a solid carrier is used for oral administration, the preparation canbe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation can be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which can be prepared using a suitable dispersant or wettingagent and a suspending agent Injectable forms can be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils can be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the formulation can also be a powder suitable forreconstitution with an appropriate solution as described above. Examplesof these include, but are not limited to, freeze dried, rotary dried orspray dried powders, amorphous powders, granules, precipitates, orparticulates. For injection, the formulations can optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these. The compounds can be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection can be in ampoules or inmulti-dose containers.

The formulations of the invention can be designed to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart. Thus, the formulations can also be formulated for controlledrelease or for slow release.

Compositions contemplated by the present invention can include, forexample, micelles or liposomes, or some other encapsulated form, or canbe administered in an extended release form to provide a prolongedstorage and/or delivery effect. Therefore, the formulations can becompressed into pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections. Such implants can employ known inertmaterials such as silicones and biodegradable polymers, e.g.,polylactide-polyglycolide. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides).

For nasal administration, the preparation can contain a compound of theinvention, dissolved or suspended in a liquid carrier, preferably anaqueous carrier, for aerosol application. The carrier can containadditives such as solubilizing agents, e.g., propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabens.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Dosage forms can be administered daily, or more than once a day, such astwice or thrice daily. Alternatively dosage forms can be administeredless frequently than daily, such as every other day, or weekly, if foundto be advisable by a prescribing physician. Dosing regimens include, forexample, dose titration to the extent necessary or useful for theindication to be treated, thus allowing the patient's body to adapt tothe treatment and/or to minimize or avoid unwanted side effectsassociated with the treatment. Other dosage forms include delayed orcontrolled-release forms. Suitable dosage regimens and/or forms includethose set out, for example, in the latest edition of the Physicians'Desk Reference, incorporated herein by reference.

An embodiment of the invention also encompasses prodrugs of a compoundof the invention which on administration undergo chemical conversion bymetabolic or other physiological processes before becoming activepharmacological substances. Conversion by metabolic or otherphysiological processes includes without limitation enzymatic (e.g.,specific enzymatically catalyzed) and non-enzymatic (e.g., general orspecific acid or base induced) chemical transformation of the prodruginto the active pharmacological substance. In general, such prodrugswill be functional derivatives of a compound of the invention which arereadily convertible in vivo into a compound of the invention.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

In another embodiment, there are provided methods of making acomposition of a compound described herein including formulating acompound of the invention with a pharmaceutically acceptable carrier ordiluent. In some embodiments, the pharmaceutically acceptable carrier ordiluent is suitable for oral administration. In some such embodiments,the methods can further include the step of formulating the compositioninto a tablet or capsule. In other embodiments, the pharmaceuticallyacceptable carrier or diluent is suitable for parenteral administration.In some such embodiments, the methods further include the step oflyophilizing the composition to form a lyophilized preparation.

The compounds of the invention can be used therapeutically incombination with i) one or more other GLP-1 modulators and/or ii) one ormore other types of therapeutic agents or second medicaments which canbe administered orally in the same dosage form, in a separate oraldosage form (e.g., sequentially or non-sequentially) or by injectiontogether or separately (e.g., sequentially or non-sequentially).Examples of combination therapeutic agents include Metformin,Sitagliptin (MK-0431, Januvia) an oral antihyperglycemic (antidiabeticdrug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class andExenatide (Byetta) an incretin mimetic. In other embodiments, the secondmedicament is a biguanide such as metformin, a sulfonylurea such asglibenclamide, glipizide, gliclazide, and glimepiride, a meglitinidesuch as repaglinide and nateglinide, a thiazolidinedione such aspioglitazone and rosiglitazone, an ca-glucosidase inhibitor such asacarbose and miglitol, a bile acid sequestrant such as colesevelam,and/or a dopamine-2 agonist such as bromocriptine.

Combinations of the invention include mixtures of compounds from i) andii) in a single formulation and compounds from i) and ii) as separateformulations. Some combinations of the invention can be packaged asseparate formulations in a kit. In some embodiments, two or morecompounds from ii) are formulated together while a compound of theinvention is formulated separately.

The dosages and formulations for the other agents to be employed, whereapplicable, will be as set out in the latest edition of the Physicians'Desk Reference, incorporated herein by reference.

In certain embodiments, the present invention encompasses compounds thatbind with high affinity and specificity to the GLP-1 receptor in anagonist manner or as an activator or a potentiator. In certainembodiments a compound of the invention acts as a positive allostericmodulator of GLP-1 receptor.

In certain embodiments, the present invention provides a method foractivating, potentiating, or agonizing (i.e., to have an agonic effect,to act as an agonist) a GLP-1 receptor, with a compound of theinvention. The method involves contacting the receptor with a suitableconcentration of an inventive compound to bring about activation of thereceptor. The contacting can take place in vitro, for example incarrying out an assay to determine the GLP-1 receptor activationactivity of an inventive compound undergoing experimentation related toa submission for regulatory approval.

In certain embodiments, the method for activating a GLP-1 receptor, canalso be carried out in vivo, that is, within the living body of amammal, such as a human patient or a test animal. The inventive compoundcan be supplied to the living organism via one of the routes asdescribed above, e.g., orally, or can be provided locally within thebody tissues. In the presence of the inventive compound, activation ofthe receptor takes place, and the effect thereof can be studied.

An embodiment of the present invention provides a method of treatment ofa malcondition in a patient for which activation of an GLP-1 receptor ismedically indicated, wherein the patient is administered the inventivecompound in a dosage, at a frequency, and for a duration to produce abeneficial effect on the patient. The inventive compound can beadministered by any suitable means, examples of which are describedabove.

In certain embodiments, the present invention is directed to compoundsadapted to act as modulators or potentiators of Class B GPCRs. Thesecompounds may have activity on their own or in the presence of receptorligands. Receptors include incretin peptides including GLP-1(7-36) andGLP-1(9-36).

Methods of treatments provided by the invention include administrationof a compound of the invention, alone or in combination with anotherpharmacologically active agent or second medicament to a subject orpatient having a malcondition for which activation, potentiation oragonism of a glucagon-like peptide 1 receptor is medically indicatedsuch as type I diabetes, type II diabetes, gestational diabetes,obesity, excessive appetite, insufficient satiety, or metabolicdisorder.

In another embodiment, methods of treatment provided by the inventioninclude administration of a compound of the invention for the treatmentof non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholicsteatohepatitis (NASH). NAFLD is believed to be caused by the disruptionof hepatic lipid homeostasis and, at least in a portion of patients, canprogress to NASH. NAFLD is associated with insulin resistance in type 2diabetes mellitus, and GLP1 increases insulin sensitivity and aidsglucose metabolism. The compounds of this invention are beneficial inthis context by serving to increase fatty acid oxidation, decreaselipogenesis, and/or improve hepatic glucose metabolism (see e.g., Leeet. al., Diabetes Metab. J. 36:262-267, 2012; Trevaskis et al. Am. J.Physiol. Gastrointest. Liver Physiol. 302:G762-G772, 2012; Kim et al.Korean J. Physiol. Pharmacol. 18:333-339, 2014; and see: Armstrong et.al., Journal of Hepatology 62:S187-S212, 2015 for results withLiraglutide in Phase II trials).

General Synthetic Methods for Preparing Compounds

Molecular embodiments of the present invention can be synthesized usingstandard synthetic techniques known to those of skill in the art.Compounds of the present invention can be synthesized using the generalsynthetic procedures set forth in Schemes 1-9.

The other enantiomer and/or diastereomers can be prepared in a similarmanner using Scheme 1.

The other enantiomer and/or diastereomers can be prepared in a similarmanner using Scheme 2.

The other enantiomer and/or diastereomers can be prepared in a similarmanner using Scheme 3.

The other enantiomer and/or diastereomers can be prepared in a similarmanner using Scheme 4.

The other enantiomer and/or diastereoisomers can be prepared in asimilar manner using Scheme 5.

The other enantiomer and/or diastereoisomers can be prepared in asimilar manner using Scheme 6.

The other enantiomer and/or diastereoisomers can be prepared in asimilar manner using Scheme 7.

The other enantiomer and/or diastereoisomers can be prepared in asimilar manner using Scheme 8.

The other enantiomer and/or diastereoisomers can be prepared in asimilar manner using Scheme 9.

The other enantiomer and/or diastereoisomers can be prepared in asimilar manner using Scheme 10.

The other enantiomer and/or diastereoisomers can be prepared in asimilar manner using Scheme 11.

Examples

The invention is further illustrated by the following examples. Theexamples below are non-limiting are merely representative of variousaspects of the invention.

Solid and dotted wedges within the structures herein disclosedillustrate relative stereochemistry, with absolute stereochemistrydepicted only when specifically stated or delineated.

General Methods

NMR Spectra

¹H NMR (400 MHz) and ¹³C NMR (100 MHz) were obtained in solution ofdeuteriochloroform (CDCl₃) or dimethyl sulfoxide (d₆-DMSO). NMR spectrawere processed using MestReNova 6.0.3-5604.

LCMS Data

Mass spectra (LCMS) were obtained using one of 6 systems. System 1a:Agilent 1100/6110 HPLC system equipped with a Thompson ODS-A, 100 A, 5μ(50×4.6 mm) column using water with 0.1% formic acid as the mobile phaseA, acetonitrile with 0.1% formic acid as the mobile phase B, water with5 mM ammonium acetate as the mobile phase C, and acetonitrile with 5 mMammonium acetate as the mobile phase D with a flow rate of 1 mL/min.Method 1: 20-100% mobile phase B (80-0% A) over 2.5 min then held at100% B for 2.5 min. Method 2: 5% mobile phase B (95% A) for 1 min, 5-95%B over 9 min, then held at 95% B for 5 min. Method 3: 20-100% mobilephase B (80-0% A) over 2.5 min then held at 100% B for 4.5 min. Method12: 5% D (95% C) for 1 min. then 5-95% D over 9 min. and held at 95% Dfor 5 min. System Ib: Agilent 1100/6110 HPLC system equipped with aAgilent Poroshell 120 EC-C8, 2.7μ (50×3 mm) column using water with 5 mMammonium acetate as the mobile phase C, and acetonitrile with 5 mMammonium acetate as the mobile phase D with a flow rate of 1 mL/min.Method 13: 5% D (95% C) to 95% D over 12 min. then held at 95% D for 2.8min. and to 5% D over 0.2 min. System 1c: Agilent 1100/6110 HPLC systemequipped with a Agilent Poroshell 120 EC-C18, 2.7μ (50×3 mm) columnusing water with 5 mM ammonium acetate as the mobile phase C, andacetonitrile with 5 mM ammonium acetate as the mobile phase D with aflow rate of 1 mL/min. Method 14: 5% D (95% C) to 95% D over 12 min.then held at 95% D for 2.8 min. and then to 5% D over 0.2 min. Method15: 20% D (80% C) to 95% D over 3 min. and hold at 95% D 1.8 min then to20% D over 0.2 min. Method 16: 20% D (80% C) to 95% D over 3.0 min. andhold at 95% D for 3.8 min. then 20% D over 0.2 min. System 1d: Agilent1100/6110 HPLC system equipped with a Agilent Poroshell 120 EC-C8, 2.7μ(50×3 mm) column using water with 5 mM ammonium acetate as the mobilephase C, and acetonitrile with 5 mM ammonium acetate as the mobile phaseD with a flow rate of 1 mL/min. Method 18: 20% D (80% C) to 95% D over 3min. and hold at 95% D 1.8 min then to 20% D over 0.2 min. Method 19:20% D (80% C) to 95% D over 3.0 min. and hold at 95% D for 3.8 min. then20% D over 0.2 min. Method 20: 5% D (95% C) to 95% D over 12 min thenheld at 95% D for 2.8 min. and then to 5% D over 0.2 min. System 1e:Agilent 1100/6110 HPLC system equipped with a Waters X-Bridge C-8, 3.5μ(50×4.6 mm) column using water with 5 mM ammonium acetate as the mobilephase C, and acetonitrile with 5 mM ammonium acetate as the mobile phaseD with a flow rate of 1 mL/min. Method 25: 20% D (80% C) to 95% D over 3min. then held at 95% D for 3.8 min. and then to 5% D over 0.2 min.Method 26: 20% D (80% C) to 95% D over 3 min. and hold at 95% D 1.8 minthen to 20% D over 0.2 min. Method 28: 20% D (80% C) to 95% D over 12.0min. and hold at 95% D for 2.8 min. then 20% D over 0.2 min. System 2:Agilent 1200 LCMS equipped with an Agilent Zorbax Extend RRHT 1.8 m(4.6×30 mm) column using water with 0.1% formic acid as mobile phase Aand acetonitrile with 0.1% formic acid as mobile phase B. Method 4:5-95% mobile phase B over 3.0 min with a flow rate of 2.5 mL/min, thenheld at 95% for 0.5 min with a flow rate of 4.5 mL/min. Method 5: 5-95%mobile phase B over 14 min with a flow rate of 2.5 mL/min, then held at95% for 0.5 min with a flow rate of 4.5 mL/min. System 3: WatersFractionlynx LCMS system equipped with an Agilent Zorbax Extend RRHT 1.8m, (4.6×30 mm) column using water with 0.1% formic acid as mobile phaseA and acetonitrile with 0.1% formic acid as mobile phase B. Method 6:5-95% mobile phase B over 3.0 min with a flow rate of 2.5 mL/min, thenheld at 95% for 0.5 min with a flow rate of 4.5 mL/min. Method 7: 5-95%mobile phase B over 14 min with a flow rate of 2.5 mL/min, then held at95% for 0.5 min with a flow rate of 4.5 mL/min. System 4: Agilent 1260LCMS equipped with an Agilent Zorbax Extend RRHT 1.8 m (4.6×30 mm)column using water with 0.1% formic acid as mobile phase A andacetonitrile with 0.1% formic acid as mobile phase B. Method 8: 5-95%mobile phase B over 3.0 min with a flow rate of 2.5 mL/min, then held at95% for 0.5 min with a flow rate of 4.5 mL/min. Method 9: 5-95% mobilephase B over 14 min with a flow rate of 2.5 mL/min, then held at 95% for0.5 min with a flow rate of 4.5 mL/min. System 5: Agilent 1260 LCMSequipped with a Waters Xselect CSH C18 3.5 m (4.6×50 mm) column usingwater with 0.1% formic acid as mobile phase A and acetonitrile with 0.1%formic acid as mobile phase B. Method 10: The gradient was 5-95% mobilephase B over 13.0 min with a flow rate of 2.5 mL/min, then held at 95%for 1.0 min with a flow rate of 4.5 mL/min. Method 11: The gradient was5-95% mobile phase B over 3.0 min with a flow rate of 2.5 mL/min, thenheld at 95% for 0.6 min with a flow rate of 4.5 mL/min. System 6: WatersAcquity UPLC system equipped with a Acquity UPLC BEH C18, 1.7 μm (2.1×50mm) or Phenomenex Kinetex C18, 1.7 μm (2.1×50 mm) column using waterwith 10 mM ammonium formate as mobile phase A, acetonitrile as mobilephase B with a flow rate of 0.5 mL/min. Method 17: 10% mobile phase B(90% A) for 0.5 min, 10-95% B over 3 min, then held at 95% B for 1.1min, 95-10% B over 0.1 min then held for 0.3 min and the total run timeis 5 min. Method 23: 20% mobile phase B (80% A) for 0.5 min, 20-95% Bover 3 min, then held at 95% B for 1.1 min, 95-20% B over 0.1 min, thenheld for 0.3 min and the total run time is 5 min. Method 24: 30% mobilephase B (70% A) for 0.5 min, 30-95% B over 2.2 min, then held at 95% Bfor 1.9 min, 95-30% B over 0.1 min, then held for 0.3 min and the totalrun time is 5 min. Method 27: 40% mobile phase B (60% A) for 0.5 min,40-95% B over 1.9 min, then held at 95% B for 2.2 min, 95-40% B over 0.1min, then held for 0.3 min and the total run time is 5 min. Method 21:20% mobile phase B (80% A) for 0.5 min, 20-95% B over 2.7 min, then heldat 95% B for 1.4 min, 95-20% B over 0.1 min, then held for 0.3 min andthe total run time is 5 min. Method 22: 40% mobile phase B (60% A) for0.5 min, 40-95% B over 1.6 min, then held at 95% B for 2.5 min, 95-40% Bover 0.1 min, then held for 0.3 min and the total run time is 5 min.

Hydrogenations

Hydrogenation reactions were performed using a Thales NanotechnologyH-Cube reactor equipped with the specified CatCart or using standardlaboratory techniques.

Reaction Conditions and Abbreviations

Pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene usedin the procedures were from Aldrich Sure-Seal bottles or Acros AcroSealdry solvent and kept under nitrogen (N₂). All reactions were stirredmagnetically and temperatures are external reaction temperatures. Thefollowing abbreviations are used: ethyl acetate (EA),1-methy-2-pyrrolidinone (NMP), triethylamine (TEA),N-hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), N,N-dimethylformamide (DMF), dimethylacetamide (DMA), Di-tert-butyl dicarbonate (Boc₂O),N,N-Diisopropylethylamine (DIEA), acetic acid (AcOH), hydrochloric acid(HCl), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), tert-butanol(t-BuOH), sodium hydride (NaH), sodium triacetoxyborohydride(Na(OAc)₃BH), ethanol (EtOH), methanol (MeOH), acetonitrile (ACN).

Purifications

Chromatographies were carried out using a Combiflash Rf flashpurification system (Teledyne Isco) equipped with Redisep (TeledyneIsco), Telos (Kinesis) or GraceResolv (Grace Davison Discovery Sciences)silica gel (SiO₂) columns. Preparative HPLC purifications were performedusing one of two systems. System 1: Varian ProStar/PrepStar systemequipped with a Waters SunFire Prep C18 OBD, 5 μm (19×150 mm) columnusing water containing 0.05% trifluoroacetic acid as mobile phase A, andacetonitrile with 0.05% trifluoroacetic acid as mobile phase B. Thegradient was 40-95% mobile phase B over 10 min, held at 95% for 5-10min, and then return to 40% over 2 min with flow rate of 18 mL/min.Fractions were collected using a Varian Prostar fraction collector by UVdetection at 254 nm and were evaporated using a Savant SpeedVac Plusvacuum pump or a Genevac EZ-2. System 2: Waters Fractionlynx systemequipped with an Agilent Prep-C18, 5 μm (21.2×50 mm) column using watercontaining 0.1% formic acid as mobile phase A, and acetonitrile with0.1% formic acid as mobile phase B. The gradient was 45-95% mobile phaseB over 7.5 min, held at 95% for 1 min, and then returned to 45% over 1.5min with a flow rate of 28 mL/min. Fractions were collected by UVdetection at 254 nm or by mass and evaporated using a Genevac EZ-2.

Chiral Methods

Chiral Method 1:

This method was used to detect enantiomeric excess of the tyrosinechiral center and not other steroecenters within the exemplifiedcompounds. Enantiomeric excess was determined by integration of peaksthat were separated on a Diacel Chiralpak IA, 4.6×250 mm column, 5 mparticle size. The solvents used were “Solvent A”: 4:1 (hexanes with0.2% TFA): DCM, and “Solvent B”: EtOH. The flow rate was held at 1.0mL/min with the following gradient: Increase Solvent B from 2-10% over30 min, hold Solvent B at 10% for 15 min.

Chiral Method 2:

Enantiomeric excess was determined by integration of peaks that wereseparated on a Daicel Chiralpak IC, 4.6×250 mm column, 5 m particle sizerunning an isocratic mixture of 76% (0.2% TFA in iso-hexanes), 19% DCMand 5% EtOH at a flow rate of 1.5 mL/min.

Chiral Preparative HPLC:

This was carried out using a Gilson preparative HPLC system equippedwith a Daicel Chiralpak IC column, 20×250 mm column, 5 μm particle sizerunning an isocratic mixture of mobile phase A (60% (0.2% TFA iniso-hexanes) and 40% DCM) at 15 mL/min and at-column-dilution withmobile phase B (EtOH) at 1.5 mL/min. Fractions were collected by UVdetection at 254 nm and evaporated using a Genevac EZ-2.

General Procedures

General Procedure 4: Hydrolysis of Esters to Acids.

To a stirring solution of ester (1 eq) in THF or dioxane and water, wasadded NaOH or LiOH (1-3 eq). The reaction mixture was stirred at up to60° C. for up to 18 h. The reaction mixture was neutralized with AcOH orHCl and either diluted with water or concentrated. If the reactionmixture was diluted with water, then HCl was added to acidify thereaction mixture to a pH of approximately 2. The resulting precipitatewas isolated by filtration to yield product which can be purified bychromatography, preparative HPLC, or used without purification. If thereaction mixture was concentrated, the crude material was diluted withDCM or EA and washed with brine. The organic layer was concentrated andpurified by chromatography or preparative HPLC to give final product.Alternatively, the crude material can be carried forward withoutpurification.

General Procedure 7: Preparation of Amides via Peptide Coupling.

A solution of amine (1.0 eq) and base (DIEA, TEA or NMM) (0-3.0 eq) inDCM or DMF (0.08-0.10 M) was treated with the appropriate carboxylicacid (1.0-1.5 eq). To this mixture was added the coupling reagent. Thecoupling reagent could be HATU (1.05-2.5 eq) optionally with DMAP(0.01-1 eq), EDC (1.5 eq) with HOBt (1.5 eq) or DMAP (0.01-1 eq), DCC(1.1 eq) with HOBt (1.1 eq) or DCC (1.5 eq) with DMAP (2.0 eq). Thereaction mixture was stirred until the reaction was complete. Thereaction was diluted with EA and washed with saturated aqueous NaHCO₃.The organic layer was dried over MgSO₄ and concentrated. The product waspurified by chromatography or alternatively can be carried on to thenext step without further purification.

General Procedure 8: Deprotection of Esters to Acids, Deprotection ofBoc-Amines, and/or Protodesilylation of Protected Alcohols

A solution of the tert-butyl ester or Boc-amine (1.00 eq) in DCM (0.06M) was treated with TFA (0.16-0.33 M) or 1-4N HCl in ether or dioxane(10.0-20.0 eq). The reaction mixture was stirred at either roomtemperature or 30 OC until complete. The solvent was removed and theproduct was purified by chromatography or preparative HPLC. Thisprocedure was also applicable for protodesilylation of tert-butyl,dimethylsilyl protected alcohols. A solution of the methyl ester (1.00eq) in dioxane (0.04-0.08 M) was treated with 1-6N aqueous HCl (10-100eq). The reaction mixture was stirred at either room temperature or 30OC until complete. The solvent was removed and the product was purifiedby chromatography or preparative HPLC.

General Procedure 9: Formation of Triflate.

A solution of the phenol (1.0 eq) in DCM (0.25 M) was treated with1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.1 eq). The reaction mixture was stirred at room temperature untilcomplete. The reaction was stirred with water and saturated aqueousNaHCO₃. The organic layers was dried and concentrated. The material waspurified by chromatography or alternatively used without purification.

General Procedure 10: Palladium-Catalyzed Coupling Reactions.

A solution of boronic acid or boronate ester (1.0-1.3 eq), halide(1.0-1.3 eq), sodium bicarbonate or sodium carbonate decahydrate(2.0-2.5 eq), anddichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) orPd(dppf)Cl₂ were combined in THF, acetonitrile, or dioxane (0.1-0.2 M)and water (0.25-0.50 M). The reaction was heated at 80 to 100° C. untilcomplete. The reaction was diluted with EA and washed with saturatedaqueous NaHCO₃. The organic layer was dried over MgSO₄ and concentrated.The product can be purified by chromatography, preparative HPLC, orcarried on to the next step without further purification.

General Procedure 13: Sulfonate or Sulfonamide formation.

To a solution of alcohol or amine in DCM (0.02 M) was added the sulfonylchloride (2 eq) and triethylamine (3 eq). The reaction was stirred atroom temperature until complete. The reaction was diluted with DCM andwashed with saturated aqueous NaHCO₃. The organic layer was dried overMgSO₄ and concentrated. The product can be purified by chromatography,preparative HPLC, or carried on to the next step without furtherpurification.

To a solution of acid in DCM (0.02 M) was added sulfonamide (2 eq), EDC(2 eq) and them DMAP (2 eq) at 0° C. The reaction mixture was stirredallowed to stir at room temperature until completion. Reaction wasdiluted with DCM and washed with saturated aqueous NaHCO₃, water andthen brine. The orgasmic layer was dried over MgSO4 and concentrated.The product can be purified by chromatography or preparative HPLC.

General Procedure 18: Deprotection of Cbz to Amine or Deprotection ofBenzyl Esters to Acids.

Conventional Hydrogenations: To a stirring solution of Cbz-protectedamine or benzyl protected ester (1.0 eq) in EA, THF, EtOH, or MeOH(0.01-0.05 M) was added Pd/C and the reaction was stirred under hydrogenuntil complete. The catalyst was filtered and the solvent was removed.The product was purified by chromatography or alternatively can becarried onto the next step without further purification.

Hydrogenation using H-cube: A solution of Cbz-protected amine or benzylprotected ester (1.0 eq) in dioxane or THF (0.01-0.03 M) was passed overa 10% Pd/C CatCart in a Thales Nanotechnology H-Cube reactor at 1mL/min. The solvent was evaporated and the product was carried to thenext step without further purification.

General Procedure 37: Ketone Coupling

To a stirring solution of aryl bromide (1 eq) in dioxane (0.06 M) wasadded ketone (1-2 eq), tosylhydrazine (1-2 eq), lithium tert-butoxide(3-5.5 eq), Pd₂dba₃ (2 mol %) and Xphos (8 mol %). The mixture washeated to 100° C. for 16 h then quenched with aqueous acetic acid andextracted with DCM. The combined organic extracts were dried over MgSO₄and solvents evaporated. The product was isolated by columnchromatography or preparative HPLC.

Synthesis of Representative Compounds

(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)-phenyl)propanoate (INT-5)

Prepared using General Procedure 9: A stirred solution of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate hydrate (25g, 64.2 mmol) in DCM (100 mL) was treated with MgSO₄ (4.01 g, 33.7mmol). After 15 min, the mixture was filtered and washed with DCM (2×20mL). The organics were treated with N-ethyl-N-isopropylpropan-2-amine(17.41 g, 134.7 mmol) and stirred. This solution was treated with1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(26.44 g, 74.01 mmol) and the mixture was allowed to stir overnight atroom temperature. The mixture was treated with water (50 mL) andsaturated aqueous NaHCO₃ (20 mL) and stirred vigorously for 10 min. Thelayers were separated and the organic layer was further washed withsaturated aqueous NaHCO₃ (2×50 mL), water (50 mL), and saturated aqueousNaHCO₃ (50 mL) and concentrated. The compound was purified bychromatography (EA/hexanes) to afford 26.85 g (79%) of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate INT-5. LCMS-ESI (m/z) calculated for C₂₂H₂₄F₃NO₇S: 503.1;found 526.1 [M+Na]⁺, t_(R)=4.12 min (Method 3).

(S)-Tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(INT-6)

A solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoateINT-5 (26.85 g, 53.4 mmol), potassium acetate (15.71 g, 160.1 mmol),bis-pinacolatoborane (27.1 g, 106.7 mmol) and DMSO (100 mL) was degassedwith a steady flow of nitrogen gas for 5 minutes. To this solution wasadded PdCl₂(dppf) (1.95 g, 2.67 mmol) and the solution further degassedand kept under an atmosphere of nitrogen. The mixture was heated at 100°C. for 18 h then cooled to room temperature and diluted with EA (50 mL)and washed with saturated aqueous NaHCO₃ (20 mL), water (3×30 mL), driedover MgSO₄, filtered, and the solvent removed under reduced pressure.The compound was purified by column chromatography to give 11.10 g (41%)of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate INT-6 as a oil. LCMS-ESI (m/z) calculated for C₂₇H₃₆BNO₆:481.3; found 504.3 [M+Na]⁺, t_(R)=4.21 min (Method 3). ¹H NMR (400 MHz,DMSO) δ 7.72 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.42-7.11 (m,6H), 4.98 (s, 2H), 4.22-4.08 (m, 1H), 3.03 (dd, J=13.7, 5.2 Hz, 1H),2.85 (dd, J=13.6, 10.1 Hz, 1H), 1.36 (s, 6H), 1.30 (s, 9H), 1.22-1.13(m, 6H).

(S)-Tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate (INT-7)

Prepared using General Procedure 10: A stirred mixture of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate INT-6 (21.7 g, 45.0 mmol) and 5-bromo-2-iodopyrimidine (15.4g, 54.0 mmol) in dioxane (400 mL) with sodium carbonate decahydrate(25.7 g, 90 mmol) in water (100 mL) was de-gassed. PdCl₂(dppf) (0.99 g,1.4 mmol) was added and the mixture further de-gassed then heated toreflux for 5 h. The mixture was allowed to cool while stirringovernight. The mixture was poured onto water (1 L) and EA (300 mL) andstirred for 30 min. The mixture was filtered and the layers wereseparated. The aqueous layer was further extracted with EA (2×200 mL)and the combined organic layers were washed with water (2×100 mL) thenbrine (50 mL), dried over MgSO₄ and concentrated. Column chromatography(EA/hexanes) gave 14.84 g (63%) of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate INT-7. LCMS-ESI (m/z) calculated for C₂₅H₂₆BrN₃O₄: 511.1;found 534.0 [M+Na]⁺, t_(R)=2.97 min (Method 11).

Tert-butyl (4-(tert-butyl)benzoyl)-L-tyrosinate

Prepared using General Procedure 7: Into a solution of4-(tert-butyl)benzoic acid (8.3 g, 46.4 mmol) in DMF (100 mL) were addedHATU (19.2 g, 50.6 mmol), TEA (17.6 mL, 126.4 mmol) and (S)-tert-butyl2-amino-3-(4-hydroxyphenyl) propanoate (10.0 g, 42.1 mmol). After 5 h,the reaction mixture was diluted with EA, washed with saturated aqueousNaHCO₃ and brine, then dried (Na₂SO₄), concentrated, and purified bychromatography (EA/hexanes) to provide 12.9 g (69%) of tert-butyl(4-(tert-butyl)benzoyl)-L-tyrosinate. LCMS-ESI (m/z) calculated forC₂₄H₃₁NO₄: 397.5; no m/z observed, t_(R)=3.59 min (Method 1). ¹H NMR(400 MHz, CDCl₃) δ 7.71-7.65 (m, 2H), 7.47-7.39 (m, 2H), 7.04 (t, J=5.7Hz, 2H), 6.78-6.70 (m, 2H), 6.59 (d, J=7.5 Hz, 1H), 4.91 (dt, J=7.5, 5.6Hz, 1H), 3.15 (qd, J=14.0, 5.6 Hz, 2H), 1.45 (s, 9H), 1.33 (s, 9H).

Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenylpropanoate (INT-12)

Prepared using General Procedure 9: Into a solution of tert-butyl(4-(tert-butyl)benzoyl)-L-tyrosinate (8.0 g, 17.9 mmol) were added DIEA(3.7 mL, 1.2 mmol) and N-Phenyl bis(trifluoromethanesulfonimide) (7.0 g,19.7 mmol). After stirring for 36 h, the reaction mixture was dilutedwith DCM then washed with 10% aqueous citric acid and saturated aqueousNaHCO₃. The organic layer was dried over Na₂SO₄, and concentrated toprovide 9.5 g (100%) tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl) propanoate INT-12, which was used without further purification.LCMS-ESI (m/z) calculated for C₂₅H₃₀F₃NO₆S: 529.6; no m/z observed,t_(R)=4.42 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 7.71-7.65 (m, 2H),7.49-7.43 (m, 2H), 7.32-7.26 (m, 2H), 7.22-7.16 (m, 2H), 6.69 (d, J=7.0Hz, 1H), 4.94 (dt, J=6.9, 5.9 Hz, 1H), 3.24 (t, J=7.1 Hz, 2H), 1.41 (s,9H), 1.33 (s, 9H).

Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(INT-13)

Into a degassed solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl) propanoate INT-12 (9.5 g, 24 mmol), KOAc (7.0 g, 72 mmol), andbis-pinacolatoborane (9.1 g, 36 mmol) in DMSO (20 mL) was addedPd(dppf)Cl₂ (0.87 g, 1 mmol). The reaction mixture was heated at 100° C.for 12 h under an atmosphere of N₂. The reaction mixture was dilutedwith EA then washed with saturated aqueous NaHCO₃ and H₂O. The organiclayer was dried over Na₂SO₄, concentrated, and purified bychromatography (EA/hexanes) to provide 7.2 g (60%) of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-propanoateINT-13. LCMS-ESI (m/z) calculated for C₃₀H₄₂BNO₅: 507.5; no m/zobserved, t_(R)=4.53 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d,J=8.0 Hz, 2H), 7.72-7.67 (m, 2H), 7.48-7.43 (m, 2H), 7.21 (d, J=8.0 Hz,2H), 6.59 (d, J=7.4 Hz, 1H), 5.05-4.92 (m, 1H), 3.27 (qd, J=13.7, 5.4Hz, 2H), 1.47 (s, 9H), 1.36 (m, 21H).

Tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-propanoate(INT-14)

Prepared using General Procedure 10: Into a degassed solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-propanoate INT-13 (1.0 g, 2.0 mmol), NaHCO₃ (420 mg, 3.9 mmol),and 5-bromo-2-iodopyrimidine (615 mg, 2.2 mmol) in 2/2/1 ACN/THF/H₂O wasadded Pd(dppf)Cl₂ (140 mg, 0.2 mmol). The reaction mixture was heated at110° C. for 1 h in a microwave reactor. The reaction mixture wasconcentrated, dissolved in DCM and washed with H₂O. The organic layerwas dried over Na₂SO₄, concentrated, and purified by chromatography(EA/hexanes) to provide 630 mg (58%) of tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoateINT-14. LCMS-ESI (m/z) calculated for C₂₈H₃₂BrN₄O₃: 538.5; no m/zobserved, t_(R)=4.66 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.84-8.78(s, 2H), 8.31 (t, J=7.0 Hz, 2H), 7.75-7.64 (m, 2H), 7.46-7.38 (m, 2H),7.30 (dd, J=12.9, 7.1 Hz, 2H), 6.65 (d, J=7.2 Hz, 1H), 5.10-4.94 (m,1H), 3.43-3.20 (m, 2H), 1.45 (s, 9H), 1.32 (s, 9H).

Tert-butyl (5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate

Prepared using General Procedure 7: Into a solution of5-(tert-butyl)thiophene-2-carboxylic acid (1.93 g, 10.0 mmol) in DMF (20mL) were added HATU (4.56 g, 12.0 mmol) and TEA (4.18 mL, 30.0 mmol).The mixture was stirred at room temperature for 30 min and(S)-tert-butyl 2-amino-3-(4-hydroxyphenyl) propanoate (2.37 g, 10.0mmol) was added. After 1 h, the reaction mixture was poured into 400 mLof ice-water and the solid was filtered. The solid was dissolved in DCMand EA, dried over MgSO₄, concentrated, and purified by chromatography(EA/hexanes) to provide 3.6 g (89%) of tert-butyl(5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate. LCMS-ESI (m/z)calculated for C₂₂H₂₉NO₄S: 403.2; found: 426.1 [M+Na]⁺, t_(R)=9.07 min(Method 2).

Tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy) phenyl) propanoate (INT-15)

Prepared using General Procedure 9: Into a solution of tert-butyl(5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate (3.52 g, 8.72 mmol)were added DIEA (4.56 mL, 26.17 mmol) and N-phenylbis(trifluoromethanesulfonimide) (3.27 g, 9.16 mmol). After stirring for18 h, the reaction mixture was diluted with DCM then washed withsaturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ andconcentrated. The crude product was purified by chromatography toprovide 4.10 g (87.6%) of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-propanoateINT-15. LCMS-ESI (m/z) calculated for C₂₃H₂₈F₃NO₆S2: 535.1; no m/zobserved, t_(R)=4.22 min (Method 3).

Tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(INT-16)

Into a degassed solution of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoateINT-15 (3.89 g, 7.26 mmol), KOAc (2.14 g, 21.79 mmol), andbis-pinacolatoborane (2.40 g, 9.44 mmol) in DMSO (50 mL) was addedPd(dppf)Cl₂ (0.27 g, 0.36 mmol). The reaction mixture was heated at 100°C. for 18 h under an atmosphere of N₂. The reaction mixture was pouredinto 600 mL of ice-water and the solid was filtered. The precipitate wasdiluted with EA, dried over MgSO₄, concentrated, and purified bychromatography (EA/hexanes) to provide 3.68 g (99%) of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate INT-16. LCMS-ESI (m/z) calculated for C₂₈H₄₀BNO₅S: 513.3; nom/z observed, t_(R)=4.51 min (Method 3).

Tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoate(INT-17)

Prepared using General Procedure 10: Into a degassed solution oftert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-16 (510 mg, 1.0 mmol) and 5-bromo-2-iodopyrimidine (570 mg, 2.0mmol) in 2/2/1 ACN/THF/saturated aqueous NaHCO₃ (10 mL) was addedPd(dppf)Cl₂ (30 mg, 0.4 mmol). The reaction mixture was heated at 120°C. for 1 h in a microwave reactor. The reaction mixture was diluted withwater (100 mL) and EA (50 mL) and filtered over Celite. The aqueouslayer was extracted with EA (3×30 mL) and the combined organic layer wasdried over MgSO₄, concentrated, and purified by chromatography(EA/hexanes) to provide 342 mg (63%) of tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateINT-17. LCMS-ESI (m/z) calculated for C₂₆H₃₀BrN₃O₃S: 543.1; found: 488.0[M-tBu+H]⁺, t_(R)=10.95 min (Method 2).

(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoicacid (INT-27)

Prepared using General Procedure 8 and INT-14: LCMS-ESI (m/z) calculatedfor C₂₄H₂₄BrN₃O₃: 482.3; found 481.1 [M−H]⁺, t_(R)=2.6 min (Method 15),and 98.7% e.e. (Chiral Method 1, isocratic with 2% Solvent A, 98%Solvent B). ¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 2H), 8.32 (d, J=8.3 Hz,2H), 7.64 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.3 Hz,2H), 6.64 (d, J=6.9 Hz, 1H), 5.16 (dd, J=12.7, 5.7 Hz, 1H), 3.42 (ddd,J=38.8, 14.0, 5.7 Hz, 2H), 1.32 (s, 9H).

Tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-propanoyl)-D-alaninate(INT-32)

Prepared using General Procedure 7: To a stirring solution of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoicacid INT-27 (1.50 g, 3.10 mmol) in DMF (15 mL) were added tert-butylD-alaninate (680.0 mg, 3.73 mmol) and Et₃N (802.3 mg, 6.2 mmol). Thereaction was stirred for 1 hour at 0° C. and then HATU (877.5 mg, 3.37mmol) in 2 mL DMF was added. The reaction was stirred for 1 hour at 0°C. and then warmed to room temperature with stirring for 18 hours. Thereaction solution was extracted with aqueous NaHCO₃ (3×20 mL). Thecombined organics were dried over MgSO₄ and evaporated. The crudeproduct was purified by column chromatography (50% EA in hexanes) toafford 1.44 g (76%) of tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-propanoyl)-D-alaninateINT-32 as a solid powder. LCMS-ESI (m/z) calculated for C₃₁H₃₇BrN₄O₄:609.6; found 610.2 [M+H]⁺, t_(R)=4.05 min. (Method 16). ¹H NMR (400 MHz,DMSO) δ 9.03 (s, 2H), 8.49 (d, J=8.7 Hz, 1H), 8.41 (d, J=7.2 Hz, 1H),8.24 (d, J=8.2 Hz, 2H), 7.73 (t, J=7.4 Hz, 2H), 7.54-7.37 (m, 4H), 4.85(td, J=10.1, 4.6 Hz, 1H), 4.16 (t, J=7.2 Hz, 1H), 3.24-2.97 (m, 2H),1.50-1.29 (m, 9H), 1.32-1.17 (m, 12H).

(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2carboxamido)-propanoic acid

Prepared using General Procedure 8: To a stirring solution of tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido) propanoate INT-17 (15.7 g, 28.8 mmol) in DCM(30 mL) was treated with TFA (30.0 g, 263.1 mmol). The reaction mixturewas stirred at room temperature for 18 hours to complete. The solventwas evaporated and then co-evaporated with toluene (3×20 mL) to removetrace TFA. The compound was dried under vacuum overnight to afford 13.7g (97%) of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoicacid as powder. LCMS-ESI (m/z) calculated for C₂₂H₂₂BrN₃O₃S: 487.1;found 488.1 [M+H]⁺, t_(R)=2.55 min. (Method 16). ¹H NMR (400 MHz, DMSO)δ 9.05 (d, J=5.0 Hz, 2H), 8.64 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.1 Hz,2H), 7.62 (d, J=3.8 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.92 (d, J=3.8 Hz,2H), 4.64 (td, J=10.5, 4.5 Hz, 1H), 3.26 (dd, J=13.8, 4.4 Hz, 1H), 3.11(dd, J=13.7, 10.7 Hz, 1H), 1.32 (s, 9H).

Methyl(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate(INT-35)

Prepared using General Procedure 7: To a stirring solution of methyl(S)-pyrrolidine-3-carboxylate (357.0 mg, 2.16 mmol) in DMF (10 mL) wereadded DIEA (465.26 mg, 3.60 mmol) and(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoicacid (700.0 mg, 1.44 mmol). The solution was cooled to 0° C. at ice bathand then HATU (677.55 mg, 2.88 mmol) in 2 mL DMF solution was slowlyadded. The reaction was stirred 1 hour at 0° C. and then warmed to RTwith stirring for 2 hours. The reaction solution was extracted with DCM(3×20 mL) and aqueous NaHCO₃ (3×10 mL). The combined organics were driedover MgSO₄ and evaporated. The final compound was purified by columnchromatography (40% DCM in hexane) to afford 501.0 mg (58%) of methyl(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl) pyrrolidine-3-carboxylate INT-35 as a powder. LCMS-ESI (m/z)calculated for C₂₈H₃₁BrN₄O₄S: 598.1; found 599.3 [M+H]⁺, t_(R)=3.553min. (Method 16). ¹H NMR (400 MHz, DMSO) δ 9.05 (d, J=1.1 Hz, 2H), 8.77(dd, J=11.5, 8.3 Hz, 1H), 8.25 (d, J=7.7 Hz, 2H), 7.72 (d, J=3.5 Hz,1H), 7.46 (d, J=8.3 Hz, 2H), 6.92 (d, J=3.8 Hz, 1H), 4.98-4.73 (m, 1H),3.88 (dd, J=10.3, 8.0 Hz, 1H), 3.71 (dd, J=15.5, 7.5 Hz, 1H), 3.50 (ddd,J=18.3, 12.2, 5.4 Hz, 2H), 3.38 (dd, J=17.3, 7.6 Hz, 1H), 3.23 (ddd,J=28.0, 15.0, 8.7 Hz, 1H), 3.18-2.85 (m, 3H), 2.17-1.96 (m, 2H), 1.87(td, J=15.2, 7.4 Hz, 1H), 1.32 (s, 9H).

Tert-butyl(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylate(INT-38)

Prepared using General Procedure 7: To a stirring solution of tert-butylazetidine-3-carboxylate (64.55 mg, 0.41 mmol) in DMF (1 mL) were addedDIEA (169.6 mg, 1.31 mmol), and(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoicacid (100.0 mg, 0.21 mmol). The solution was cooled to 0° C. at ice bathand then HATU (74.11 mg, 1.31 mmol) in 1 mL DMF solution was slowlyadded. The reaction was stirred 1 hour at 0° C. and then warmed to RTwith stirring for 2 hours. The reaction solution was extracted with DCM(3×10 mL) and aqueous NaHCO₃ (3×10 mL). The combined organics were driedover MgSO₄ and evaporated to afford 117.6 mg (85%) of tert-butyl(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl) azetidine-3-carboxylate INT-38 as a solid powder withoutfurther purification for next step. LCMS-ESI (m/z) calculated forC₃₀H₃₅BrN₄O₄S: 626.2; found 627.2 [M+H]⁺, t_(R)=3.884 min. (Method 16).¹H NMR (400 MHz, DMSO) δ 9.03 (d, J=1.0 Hz, 2H), 8.66 (dd, J=30.6, 8.1Hz, 1H), 8.25 (dd, J=8.1, 6.1 Hz, 2H), 7.82-7.60 (m, 1H), 7.44 (dd,J=8.2, 4.5 Hz, 2H), 6.91 (dd, J=3.8, 1.2 Hz, 1H), 4.77-4.49 (m, 1H),4.36 (t, J=8.9 Hz, 0.5H), 4.31-4.24 (m, 0.5H), 4.20 (t, J=8.8 Hz, 0.5H),4.06-3.94 (m, 1H), 3.93-3.83 (m, 1H), 3.78 (dd, J=9.6, 6.1 Hz, 0.5H),3.44-3.30 (m, 1H), 3.06 (tdd, J=13.6, 11.5, 5.4 Hz, 2H), 1.40 (d, J=5.7Hz, 4H), 1.35-1.27 (m, 14H).

(S)-tert-butyl1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-2-carboxylate(INT-54)

Prepared using General Procedure 7: To a stirred solution of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid (1.0 g, 2.05 mmol) in DMF (5 mL) at 0° C. was added DIPEA(2.14 mL, 12.28 mmol) followed by tert-butyl-L-prolinate hydrochloride(0.468 g, 2.25 mmol). To the mixture was added HATU (0.856 g, 2.25 mmol)dissolved in DMF (1.5 mL), portion wise, over 10 minutes. The reactionwas allowed to warm to room temperature and stirred overnight. Thereaction was diluted with saturated sodium bicarbonate solution andextracted with DCM (3×30 mL). The combined organic layers were driedover MgSO₄ and solvents evaporated. The crude product was purified bycolumn chromatography (0-40% EtOAc/Hexanes) to afford 1.06 g (81%) of(S)-tert-butyl1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido) propanoyl)pyrrolidine-2-carboxylate (INT-54).LCMS-ESI (m/z) calculated for C₃₁H₃₇BrN₄O₄S: 640.2; found 641.3 [M+H]⁺,t_(R)=10.63 min (Method 14). ¹H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H),8.70 (d, J=8.4 Hz, 1H), 8.23 (d, J=9.1 Hz, 2H), 7.68 (d, J=3.9 Hz, 1H),7.52 (d, J=8.3 Hz, 2H), 6.90 (d, J=3.8 Hz, 1H), 4.97-4.84 (m, 1H), 4.23(m, 1H), 3.83-3.62 (m, 2H), 3.09 (m, 2H), 2.18 (m, 1H), 1.96 (m, 2H),1.82 (m, 1H), 1.39-1.28 (m, 18H).

Tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alaninate

Prepared using General Procedure 7: To a stirring solution of tert-butylD-alaninate (5.60 g, 30.80 mmol) in DMF (50 mL) were added DIEA (8.29 g,64.18 mmol) and(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)-propanoicacid (12.5 g, 25.67 mmol). The solution was cooled to 0° C. at ice bathand then HATU (9.06 g, 38.50 mmol) in 15 mL DMF solution was slowlyadded. The reaction was stirred 1 hour at 0° C. and then warmed to RTwith stirring for 2 hours. The reaction solution was extracted with DCM(3×50 mL) and aqueous NaHCO₃ (3×30 mL). The combined organics were driedover MgSO₄ and evaporated. The final compound was purified by columnchromatography (40% DCM in hexane) to afford 14.7 g (94%) of tert-butyl((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alaninateas solid powder. LCMS-ESI (m/z) calculated for C₂₉H₃₅BrN₄O₄S: 614.2;found 615.3 [M+H]⁺, t_(R)=3.914 min. (Method 16). ¹H NMR (400 MHz,CDCl₃) δ 8.83 (d, J=3.6 Hz, 2H), 8.36 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2Hz, 2H), 7.34 (d, J=3.8 Hz, 1H), 6.81 (d, J=3.8 Hz, 1H), 6.66 (d, J=7.6Hz, 1H), 6.34 (d, J=7.2 Hz, 1H), 4.88 (d, J=5.9 Hz, 1H), 4.41 (t, J=7.2Hz, 1H), 3.31 (dd, J=13.6, 5.8 Hz, 1H), 3.20 (dd, J=13.6, 7.8 Hz, 1H),1.51-1.32 (m, 18H), 1.27 (d, J=7.1 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ172.02, 171.31, 162.28, 162.13, 161.42, 158.55, 142.27, 136.34, 134.66,130.20, 128.82, 127.92, 123.07, 118.63, 80.90, 54.45, 48.86, 39.59,39.38, 32.39, 28.04, 17.68.

(2R)-tert-butyl2-((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanamido)propanoate

Prepared using General Procedure 10: A stirred solution of(R)-tert-butyl2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido) propanamido)propanoate (0.15 g, 0.244 mmol) and(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)boronic acid (0.061 g, 0.244mmol) in dioxane (12 mL) was treated with sodium hydrogencarbonate (0.54mL of a 0.9 M aqueous solution, 0.487 mmol), warmed to 40° C. andde-gassed. PdCl₂dppf (7.13 mg, 9.75 μmol) was charged, the mixturede-gassed, then heated under reflux for 3 h. The reaction was allowed tocool to RT, poured onto water (50 mL) and extracted with EA (3×50 mL).The combined organic extracts were dried over Na₂SO₄ and evaporated.Column chromatography (EA/iso-hexanes) gave 142 mg (78%) of a mixture ofdiastereomers (2R)-tert-butyl2-((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanamido)propanoate as an off-white solid.LCMS-ESI (m/z) calculated for C₄₄H₆₀N₄O₄S: 741.1; no m/z observed,t_(R)=3.49 min (Method 11).

(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoicacid

Prepared using General Procedure 8: To a stirring solution of tert-butyl(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoateINT-7 (3.0 g, 5.8 mmol) in DCM (20 mL) was treated with TFA (10 mL). Thereaction mixture was stirred at room temperature for 18 h. The solventwas evaporated and then co-evaporated with toluene (3×20 mL) to removeresidual TFA. The compound was dried under vacuum overnight to afford13.7 g (97%) of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoicacid as powder. LCMS-ESI (m/z) calculated for C₂₁H₁₈BrN₃O₄: 456.30;found 457.43 [M+H]⁺, t_(R)=2.21 min (Method 16).

Tert-butyl(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate

Prepared using General Procedure 7: To a stirred solution of(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoicacid (6.0 g, 12.2 mmol) in DMF (20 mL) at 0° C. was added DIPEA (15.8 g,122 mmol) followed by tert-butyl azetidine-3-carboxylate hydrochloride(2.85 g, 14.7 mmol). To the mixture was added HATU (14 g, 36 mmol)slowly in three portions with 30 minute intervals. The reaction wasallowed to stir at 0° C. for 2 h and then allowed to warm to RT over 2h. Then the reaction mixture was diluted with saturated sodiumbicarbonate solution (25 mL), water (25 mL) and EA (100 mL). The layerswere separated and the aqueous layer was extracted with EA (2×100 mL).The combined organic layers were washed with water, brine and then driedover MgSO₄ and concentrated. The crude product was purified by columnchromatography (0-40% EA/Hexanes) to afford 4.6 g (60%) of tert-butyl(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate.LCMS-ESI (m/z) calculated for C₂₉H₃₁BrN₄O₅: 595.5; found 596.6 [M+H]+,t_(R)=3.59 min (Method 16).

Tert-butyl1-((2S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate

Prepared using General Procedure 10: A stirred solution of tert-butyl(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoyl) azetidine-3-carboxylate (1.5 g, 2.52 mmol) and(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)boronic acid (0.76 g, 3.02mmol) in 3:1 mixture of dioxane and water (20 mL) was treated withsodium carbonate (0.30 g, 5.0 mmol) and the mixture was de-gassed for 5min. PdCl₂dppf (0.18 g, 0.25 mmol) was charged, the mixture wasde-gassed again for 2 min, then heated at 70° C. for 7 h. The reactionmixture was allowed to cool to RT and then diluted with EA (20 mL) andwater (20 mL). The layers were separated and the aqueous layer wasextracted with EA (3×50 mL). The combined organic extracts were driedover MgSO₄ and solvent evaporated. Column chromatography of crudeproduct (0-60% EA/Hexanes) gave 1.56 g (85%) of a mixture ofdiastereomers tert-butyl1-((2S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylateas an off-white solid. LCMS-ESI (m/z) calculated for C₄₄H₅₆N₄O₅: 720.95;found 721.63 [M+H]⁺, t_(R)=7.02 min (Method 16).

Tert-butyl1-((2S)-2-amino-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(INT-64)

Prepared using General Procedure 18. To a stirring solution of adiastereomeric mixture of tert-butyl1-((2S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(1.0 g, 1.38 mmol) in EA (40 mL) was added Pd/C (0.1 g, 0.1 mmol) andthe reaction was flushed with hydrogen gas three times. The reactionmixture was stirred under an atmosphere of hydrogen for 36 hours, themixture was filtered over Celite, and then concentrated to give 0.75 g(92%) of a mixture of diastereomers tert-butyl1-((2S)-2-amino-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(INT-64) as gray solid. The material was used without furtherpurification. LCMS-ESI (m/z) calculated for C₃₆H₅₀N₄O₃: 586.8 found587.4 [M+H]⁺, t_(R)=5.82 min (Method 16). This material contains ˜10%olefin reduced bi-product, tert-butyl(S)-1-(2-amino-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylateand could not be separated by column chromatography. LCMS-ESI (m/z)calculated for C₃₆H₅₂N₄O₃: 588.82; found 589.4 [M+H]⁺, t_(R)=5.58 min(Method 16).

Methyl(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylate

Prepared using General Procedures 7: To a stirred solution of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoicacid (3.85 g, 7.90 mmol) in DMF (50 mL), treated with methylazetidine-3-carboxylate hydrochloride (3.59 g, 23.69 mmol) and cooled to−5° C. whereupon DIEA (8.75 mL, 47.4 mmol) was added. When a clearsolution was observed, HATU (7.51 g, 19.74 mmol) was added portionwise,to maintain internal temperature between 0 and −5° C. After 15 min,further HATU (0.75 g, 1.97 mmol) was charged. After a further 30 min themixture was quenched with water (2 mL) and allowed to warm to roomtemperature. The mixture was diluted with water (˜30 mL) and acidifiedwith AcOH. The precipitate was collected by filtration, washingsuccessively with water (3×30 mL) then ACN (2×5 mL) to afford 4.25 g(92%) of methyl(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl) azetidine-3-carboxylate. LCMS-ESI (m/z) calculated forC₂₇H₂₉BrN₄O₄S: 584.1; found 585.0 [M+H]⁺, t_(R)=2.55 min (Method 11).

(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylicacid (INT-71)

To a stirred mixture of water (140 mL) and AcOH (140 mL) was addedsulfuric acid (53.2 mL, 993 mmol) and the mixture allowed to cool toroom temperature. This was then added to a stirred solution of(S)-methyl1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl) azetidine-3-carboxylate (19.39 g, 33.1 mmol) in dioxane (225mL). After 20 h, the mixture was diluted with ice water (500 mL) andextracted with DCM (2×350 mL). The combined organic extracts were washedwith water (2×500 mL) dried over MgSO₄ and solvents evaporated. Columnchromatography (DCM/EA/AcOH) gave 12.96 g (69%) of(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylicacid INT-71. LCMS-ESI (m/z) calculated for C₂₆H₂₇BrN₄O₄S: 570.1; found571.0 [M+H]⁺, t_(R)=2.36 min (Method 11).

((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alanine(INT-72)

Prepared using General Procedure 8: To a stirred solution of(R)-tert-butyl2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanamido) propanoate (4.8 g, 7.80 mmol) in DCM (150 mL) was added TFA(18 mL). After 16 h, the reaction was diluted with toluene (100 mL) andsolvents evaporated to afford 4.36 g (100%) of((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alanineINT-72. LCMS-ESI (m/z) calculated for C₂₅H₂₇BrN₄O₄S: 558.1; no m/zobserved, t_(R)=2.43 min (Method 11).

((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanine(Compound 1)

Prepared using General Procedure 8: To a stirring solution of adiastereomeric mixture of (2R)-tert-butyl2-((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanamido)propanoate (136 mg, 0.184 mmol) in DCM(10 mL) was added TFA (1.7 mL, 22 mmol). After 16 h, the reaction wasdiluted with toluene (10 mL) and solvents evaporated. The mixture wasfurther co-evaporated with toluene (2×10 mL) to give a pale brown glass.Column chromatography (EA/AcOH/DCM/iso-hexanes) gave 94 mg (75%) of amixture of diastereomers(2R)-2-((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanamido)propanoic acid (Compound 1) as a cream solid. LCMS-ESI (m/z) calculatedfor C₄₀H₅₂N₄O₄S: 684.4; no m/z observed, t_(R)=12.15 min (Method 10).Chiral analysis showed 92.8% d.e. t_(R)=21.00 min (Chiral Method 1). ¹HNMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.90 (s, 2H), 8.51 (d, J=8.7 Hz,1H), 8.44 (d, J=7.4 Hz, 1H), 8.31-8.20 (m, 2H), 7.67-7.65 (m, 1H),7.51-7.44 (m, 2H), 6.91 (dd, J=3.9, 2.0 Hz, 1H), 6.44 (br s, 1H), 4.80(td, J=9.5, 4.4 Hz, 1H), 4.25 (p, J=7.1 Hz, 1H), 3.17-2.95 (m, 2H),2.47-2.18 (m, 2H), 1.99-1.92 (m, 2H), 1.83-1.75 (m, 4H), 1.44-0.78 (m,28H).

Compound 2 was prepared from (R)-tert-butyl2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanamido)propanoate using General Procedures 10 then 8.

Compound 3 was prepared from INT-35 using General Procedures 10 then 4.

1-((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-pentyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid (Compound 4)

Prepared using General Procedures 10 and 8: A stirring solution of(4′-pentyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)boronic acid (200.3 mg, 0.72mmol), sodium carbonate decahydrate (57.6 mg, 0.96 mmol), tert-butyl(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylate INT-38 (300.0 mg, 0.48 mmol) andPd(dppf)Cl₂ (35.1 mg, 0.048 mmol) in dioxane (9 mL) and water (3 mL) wasdegassed by nitrogen and was heated to 60° C. for 2 hours. The reactionsolution was evaporated under reduced pressure and then diluted with DCM(20 mL). The crude material was extracted with aqueous NaHCO₃ (3×20 mL).The combined organics were dried over MgSO₄ and the solvent wasevaporated. The crude product was purified by column chromatography (50%EA in hexanes) to afford 302.5 mg (80.8%) of tert-butyl1-((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-pentyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate as anintermediate. The intermediate was dissolved in DCM (10 ml) and treatedwith 5.0 mL of TFA and stirred at room temperature for 18 hours. Theproduct was co-evaporated with CH₃CN (5×10 mL) to afford 268.2 mg (77%)of a mixture of diastereomers1-((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-pentyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid (Compound 4) as a solid powder. LCMS-ESI(m/z) calculated for C₄₃H₅₆N₄O₄S: 724.4; found 725.3 [M+H]⁺, t_(R)=12.55min. (Method 14); ¹H NMR (400 MHz, DMSO) δ 8.90 (d, J=1.0 Hz, 2H), 8.70(d, J=8.1 Hz, 1H), 8.27 (dd, J=8.1, 4.6 Hz, 2H), 7.69 (d, J=3.9 Hz, 1H),7.43 (d, J=8.0 Hz, 2H), 6.92 (d, J=3.8 Hz, 1H), 6.42 (s, 1H), 4.76-4.54(m, 3H), 4.43 (t, J=8.8 Hz, 1H), 4.37-4.23 (m, 1H), 4.17 (dd, J=18.4,7.7 Hz, 1H), 4.11-3.96 (m, 2H), 3.95-3.77 (m, 1H), 3.38 (d, J=44.3 Hz,1H), 3.18-2.94 (m, 2H), 2.40 (s, 1H), 2.27 (d, J=18.8 Hz, 1H), 1.97 (d,J=18.0 Hz, 2H), 1.86-1.63 (m, 4H), 1.46-1.19 (m, 16H), 1.15 (s, 4H),0.98 (dd, J=24.6, 11.9 Hz, 2H), 0.8-0.95 (m, J=7.0 Hz, 4H). ¹³C NMR (101MHz, DMSO) δ 173.44, 170.43, 162.00, 161.32, 160.81, 153.27, 140.57,135.44, 135.27, 131.62, 130.53, 129.53, 129.49, 128.47, 127.22, 122.66,52.60, 50.29, 50.17, 41.77, 39.52, 39.31, 39.10, 38.89, 38.02, 37.25,34.36, 32.94, 31.88, 31.56, 29.54, 29.32, 29.28, 26.30, 25.97, 25.68,22.04, 13.86.

Compounds 5 and 8 were prepared from INT-54 using General Proceduresthen 8.

1-((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid (Compound 6)

Prepared using General Procedure 10 and 8: To a stirring solution of(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)boronic acid (31.9 mg, 0.13mmol), sodium carbonate decahydrate (7.8 mg, 0.13 mmol), tert-butyl(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-azetidine-3-carboxylate INT-38 (40.0 mg, 0.064 mmol) andPd(dppf)Cl₂ (46.8 mg, 0.048 mmol) in dioxane (3 mL) and water (1.0 mL).The reaction solution was degassed by nitrogen and was heated to 60° C.for 2 hours. The reaction solvent was evaporated under reduced pressureand then diluted in DCM (10 mL). The crude material was extracted withaqueous NaHCO₃ (2×3 mL). The combined organics were dried over MgSO₄ andthe solvent was evaporated. To the crude material in 1 ml DCM was added0.1 mL of TFA and stirred at room temperature for 18 hours. The finalproduct was purified by HPLC to afford 1.14 mg (2.6%) of a mixture ofdiastereomers1-((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid (Compound 6) as a solid. LCMS-ESI (m/z)calculated for C₄₁H₅₂N₄O₄S: 696.4; found: 697.4[M+H]⁺, t_(R)=11.38 min.(Method 14). Chiral analysis showed 97.2% d.e. t_(R)=21.01 min (ChiralMethod 1); ¹H NMR (400 MHz, DMSO) δ 12.59 (s, 1H), 8.90 (d, J=1.5 Hz,2H), 8.68 (dd, J=8.2, 2.6 Hz, 0.9H), 8.56 (d, J=8.0 Hz, 0.1H), 8.26 (dd,J=8.1, 4.5 Hz, 2H), 7.68 (d, J=3.9 Hz, 0.8H), 7.61 (d, J=3.8 Hz, 0.2H),7.42 (d, J=7.9 Hz, 2H), 6.91 (d, J=3.8 Hz, 1H), 6.42 (s, 1H), 4.64 (dd,J=11.5, 6.3 Hz, 1H), 4.43-4.2 (m, 0.5H), 4.33-4.22 (m, 0.5H), 4.23-4.09(m, 1H), 4.09-3.95 (m, 1H), 3.96-3.79 (m, 1H), 3.47-3.37 (m, 1H),3.07-3.08 (m, 2H), 2.53-2.52 (m, 0.5H), 2.32 (dd, J=45.3, 16.2 Hz,2.5H), 1.97 (d, J=18.6 Hz, 2H), 1.86-1.65 (m, 4H), 1.43-1.20 (m, 13H),1.21-1.07 (m, 4H), 0.99 (dt, J=24.4, 12.2 Hz, 2H), 0.92-0.77 (m, 5H).¹³C NMR (101 MHz, DMSO) δ 173.44, 172.90, 170.44, 162.00, 161.31,160.82, 153.25, 140.56, 135.48, 135.28, 135.25, 131.60, 130.52, 129.53,129.48, 129.35, 128.47, 127.23, 127.19, 127.14, 122.65, 53.65, 52.61,50.30, 50.17, 41.78, 38.02, 36.96, 36.31, 36.19, 32.90, 31.88, 31.58,29.53, 29.31, 29.28, 28.96, 26.31, 25.68, 19.42, 14.20.

1-((2R)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid (Compound 81) was prepared using similarprocedures. Chiral analysis showed 97.3% e.e. at the Tyrosine chiralcenter. t_(R)=14.84 min (Chiral Method 1).

(3S)-1-((25)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylicacid (Compound 7)

Prepared using General Procedure 10 and 4. To a stirring solution of(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)boronic acid (31.9 mg, 0.13mmol), sodium carbonate decahydrate (7.8 mg, 0.13 mmol), methyl(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-pyrrolidine-3-carboxylateINT-35 (38.9 mg, 0.064 mmol) and Pd(dppf)Cl₂ (46.8 mg, 0.048 mmol) indioxane (3 mL) and water (1.0 mL). The reaction solution was degassed bynitrogen and was heated to 60° C. for 2 hours. The reaction solvent wasevaporated under reduced pressure and then diluted in DCM (5 mL). Thecrude material was extracted with aqueous NaHCO₃ (2×1 mL). The combinedorganics were dried over MgSO₄ and the solvent was evaporated. The crudematerial was dissolved in 1 ml MeOH and 0.1 mL of aqueous 1N NaOH andstirred at room temperature for 18 hours. The final product was purifiedby HPLC to afford 0.52 mg (1.1%) of a mixture of diastereomers(3S)-1-((2S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)-propanoyl)pyrrolidine-3-carboxylicacid (Compound 7) as a solid. LCMS-ESI (m/z) calculated for C₄₂H₅₄N₄O₄S:710.4; found: 711.4 [M+H]⁺, t_(R)=11.84 min. (Method 14). ¹H NMR (400MHz, DMSO) δ 12.47 (s, 1H), 8.90 (s, 2H), 8.70 (d, J=7.9 Hz, 1H), 8.26(d, J=7.9 Hz, 2H), 7.71 (s, 1H), 7.56-7.12 (m, 2H), 6.91 (d, J=3.8 Hz,1H), 6.42 (s, 1H), 5.06-4.68 (m, 1H), 3.69 (d, J=7.6 Hz, 0.5H),3.63-3.50 (m, 1.5H), 3.43 (dd, J=17.0, 10.2 Hz, 1H), 3.05 (ddd, J=23.8,16.8, 8.0 Hz, 4H), 2.42-2.17 (m, 2H), 1.97 (dd, J=28.0, 9.5 Hz, 4H),1.86-1.61 (m, 4H), 1.50-1.21 (m, 13H), 1.21-1.09 (m, 4H), 1.00 (dt,J=24.7, 12.2 Hz, 3H), 0.92-0.78 (m, 5H).

Compound 9 was prepared from INT-17 using General Procedures 10 then 8.

Compound 10 was prepared from INT-17 using General Procedures 10, 7 then8.

Compound 11 was prepared from INT-38 using General Procedures 10 then 8.

Compounds 13, 15, 17, 19, 21-24, 26, 27, 29, 30, 32, 33, 34 and 35 wereprepared from INT-64 using General Procedures 7 then 8.

1-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-((1RS,1′s,4′RS)-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid (Compound 14)

Prepared using General Procedure 10: To stirring solution of(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoyl)azetidine-3-carboxylic acid (made from INT-27 using General Procedure 7followed by General Procedure 4) (21.3 g, 37.7 mmol) and racemic(1RS,1′s,4′RS)-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)boronic acid(11.66 g, 45.2 mmol) in dioxane (500 mL) was added a solution of sodiumhydrogencarbonate (105 mL of a 0.9 M aqueous solution, 94 mmol). Themixture was warmed to 40° C. and degassed. PdCl₂dppf (1.230 g, 1.51mmol) was added and the mixture heated at 95° C. for 1.5 h. The mixturewas allowed to cool then diluted with 1 M HCl (400 mL) and extractedwith EA (2×500 mL). The combined organic extracts were evaporated. Theresidue was purified by column chromatography (THF/AcOH/iso-hexanes/DCM)then re-slurry from ACN to afford 16.42 g (63%) of a mixture ofdiastereomers1-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-((1R,1′s,4′RS)-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl) propanoyl) azetidine-3-carboxylic acid. LCMS-ESI(m/z) calculated for C₄₃H₅₄N₄O₄: 690.4; no m/z observed, t_(R)=3.46 min(Method 11). Chiral analysis (Chiral Method 1) showed >95% single peak.¹H NMR (400 MHz, DMSO-d₆) δ 12.71 (s, 1H), 8.91 (s, 2H), 8.74-8.68 (m,1H), 8.30-8.24 (m, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.49-7.41 (m, 4H), 6.43(s, 1H), 4.74-4.65 (m, 1H), 4.45 (app t, J=8.6 Hz, 0.5H), 4.34-4.27 (m,0.5H), 4.25-4.13 (m, 1H), 4.10-3.98 (m, 1H), 3.96-3.85 (m, 1H),3.48-3.40 (m, 1H), 3.17-3.02 (m, 2H), 2.45-2.21 (m, 2H), 2.02-1.87 (m,2H), 1.85-1.69 (m, 4H), 1.42-0.78 (m, 25H).

1-((S)-2-(5-ethylthiophene-2-carboxamido)-3-(4-(5-((1RS,1′s,4′RS)-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid (Compound 31)

Prepared using General Procedure 10: A stirring mixture of(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-ethylthiophene-2-carboxamido)propanoyl)azetidine-3-carboxylic acid (4.4 g, 8.10 mmol) (from INT-73 usingGeneral Procedure 8) and racemic(1RS,1′s,4′RS)-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)boronic acid(2.228 g, 8.91 mmol) in dioxane (100 mL) and NaHCO₃ (27.0 mL, of a 0.9 Maqueous solution, 24.29 mmol) was warmed to 40° C. and de-gassed.PdCl₂dppf (0.178 g, 0.24 mmol) was charged and the mixture heated underreflux. After 6 h, the mixture was diluted with water (200 mL) andacidified with acetic acid (3.41 mL, 48.6 mmol). After stirring for 1 h,the precipitate was collected by filtration, washed with water (2×30 mL)then MeOH (20 mL). The residue was purified by column chromatography(AcOH/EtOAc/DCM) then re-slurried from MeOH (100 mL) to afford 4.1 g(76%) of a mixture of diastereomers1-((S)-2-(5-ethylthiophene-2-carboxamido)-3-(4-(5-((1RS,1′s,4′RS)-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid. LCMS-ESI (m/z) calculated for C₃₉H₄₈N₄O₄S: 688.3; no m/z observed,t_(R)=11.44 min (Method 10). Chiral analysis (Chiral Method 1)showed >95% single peak. ¹H NMR (400 MHz, DMSO-d₆) δ 12.70 (s, 1H), 8.91(app d, J=1.7 Hz, 2H), 8.73 (app dd, J=8.3, 2.2 Hz, 1H), 8.40-8.20 (m,2H), 7.70 (d, J=3.7 Hz, 1H), 7.43 (app dd, J=8.3, 1.4 Hz, 2H), 6.87 (appdd, J=3.7, 1.2 Hz, 1H), 6.54-6.35 (m, 1H), 4.67-4.60 (m, 1H), 4.45 (t,J=8.0 Hz, 0.5H), 4.31-4.27 (m, 0.5H), 4.25-4.10 (m, 1H), 4.08-3.98 (m,1H), 3.93-3.85 (m, 1H), 3.47-3.39 (m, 0.5H), 3.33-3.27 (m, 0.5H),3.18-2.95 (m, 2H), 2.79 (q, J=7.5 Hz, 2H), 2.55-2.26 (m, 3H), 2.00-1.92(m, 2H), 1.83-1.74 (m, 4H), 1.35-1.11 (m, 11H), 1.11-0.95 (m, 2H),0.91-0.84 (t, J=7.3 Hz, 5H).

Compounds 12, 16, 18, 20, 25, and 28 were prepared from tert-butyl(S)-1-(2-amino-3-(4-(5-(4′-propyl-[1,1′-bi(cyclohexan)]-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate using General Procedures 7 then 8.

Compounds 36-40, and 77 were prepared from INT-71 using GeneralProcedure 10.

Compound 41 was prepared from INT-71 using General procedures 10 and 18sequentially.

Compounds 43, 45-47 and 48 were prepared from INT-71 using Generalprocedure 37.

1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-((1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid (Compound 44)

Prepared using General Procedure 10: To a stirring solution of(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl) azetidine-3-carboxylic acid INT-71 (3.14 g, 5.50 mmol) andracemic4,4,5,5-tetramethyl-2-((1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolane(1.84 g, 6.05 mmol) in dioxane (110 mL) was added NaHCO₃ (18.3 mL of a0.9 M aqueous solution, 16.49 mmol). The mixture was degassed andtreated with PdCl₂(dppf) (0.201 g, 0.28 mmol) then heated under refluxfor 4 h. The mixture was allowed to cool then diluted with 1 M HCl (100mL) and extracted with EA (3×150 mL). The combined organic extracts weredried over MgSO₄ and solvents evaporated. Column chromatography(AcOH/EA/DCM/iso-hexanes) then re-slurry from ACN then DCM/iso-hexanesgave 2.78 g (76%) of a mixture of diastereomers1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-((1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid. LCMS-ESI (m/z) calculated for C₃₉H₄₈N₄O₄S:688.3; no m/z observed, t_(R)=11.03 min (Method 10). Chiral analysis(Chiral Method 1) showed >95% single peak. ¹H NMR (400 MHz, DMSO-d₆) δ12.74 (s, 1H), 8.91 (d, J=1.9 Hz, 2H), 8.75 (dd, J=8.5, 2.9 Hz, 1H),8.32-8.18 (m, 2H), 7.69 (d, J=3.9 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 6.92(dd, J=3.9, 1.6 Hz, 1H), 6.51-6.36 (m, 1H), 4.79-4.55 (m, 1H), 4.52-3.77(m, 4H), 3.49-3.37 (m, 0.5H), 3.34-3.31 (m, 0.5H), 3.17-2.95 (m, 2H),2.59-2.19 (m, 3H), 2.10-1.85 (m, 2H), 1.86-1.58 (m, 4H), 1.45-1.20 (m,12H), 1.17-0.71 (m, 8H).

Compounds 49-66 and 69 were prepared from INT-72 using General procedure10.

Compound 67 was prepared from INT-72 using General procedures 10 and 18sequentially.

Compound 70 was prepared from INT-72 using General procedure 37.

Compounds 71, 73, 74 and 75 were prepared from Compound 9 using GeneralProcedures 7 then 8.

1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid (Compound 76)

Prepared using General Procedure 10: To a stirring solution of(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl) azetidine-3-carboxylic acid INT-71 (5.5 g, 9.62 mmol) andracemic2-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3.37 g, 10.59 mmol) in dioxane (100 mL) was added a solution of NaHCO₃(2.021 g, 24.06 mmol) in water (100 mL) and the mixture de-gassed.PdCl₂(dppf) (0.352 g, 0.48 mmol) was added and the mixture heated underreflux for 1 h. The mixture was allowed to cool then diluted with water(200 mL), acidified with AcOH and extracted with EA (2×150 mL). Thecombined organic extracts were evaporated and the residue purified bycolumn chromatography (AcOH/EA/DCM/iso-hexanes) then re-slurry from ACNto afford 5.7 g (87%) of a mixture of diastereomers1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylicacid. LCMS-ESI (m/z) calculated for C₄₀H₅₀N₄O₄S: 682.4; found 683.4[M+H]⁺, t_(R)=3.41 min (Method 11). Chiral analysis (Chiral Method 1)showed >95% single peak. ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (s, 1H), 8.90(app d, J=1.8 Hz, 2H), 8.74 (app dd, J=8.3, 2.9 Hz, 1H), 8.32-8.20 (m,2H), 7.68 (d, J=3.9 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 6.91 (app dd,J=3.9, 1.5 Hz, 1H), 6.51-6.30 (m, 1H), 4.64 (tt, J=9.4, 4.5 Hz, 1H),4.42 (t, J=8.0 Hz, 0.5H), 4.29 (dd, J=8.7, 6.1 Hz, 0.5H), 4.24-4.10 (m,1H), 4.07-3.98 (m, 1H), 3.94-3.85 (m, 1H), 3.42 (ddd, J=15.2, 9.2, 6.0Hz, 0.5H), 3.31-3.27 (m, 0.5H), 3.13-2.99 (m, 2H), 2.53-2.24 (m, 3H),1.98-1.91 (m, 2H), 1.82-1.75 (m, 4H), 1.36-1.29 (m, 10H), 1.23-0.78 (m,12H).

Compound 72 was prepared from Compound 9 using General Procedures 7, 4then 8.

Compound 78 and 80 were prepared from Compound 9 using GeneralProcedures 7 then 4.

Compound 79 was prepared from Compound 9 using General Procedure 13.

Compound 82 was prepared from (S)-tert-butyl3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateINT-17 using General Procedures 8, 10, 7 and 8 sequentially.

(1s,4s)-4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexan-1-ol

To a stirring solution of L-selectide (7.24 mL of a 1.0 M solution inTHF, 7.24 mmol) was added a solution of4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone (1.15 g, 4.83 mmol) inTHF (10 mL). The resulting reaction mixture was stirred for 3 h. Thereaction mixture was quenched with water (1 mL) and EtOH (4 mL). After 5min stirring, 2 M NaOH (9 mL) was added followed by slow addition of 30%aqueous H₂O₂ (4 mL). After 5 min, saturated aqueous Na₂CO₃ (10 mL) wasadded. The mixture was extracted with Et₂O (3×10 mL), dried over MgSO₄,filtered and solvents evaporated. The residue was purified by columnchromatography (EA/iso-hexane) to afford 748 mg (65%) of(1s,4s)-4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexan-1-ol as a whitesolid.

8-((1s,4s)-4-ethoxycyclohexyl)-1,4-dioxaspiro[4.5]decane

To a stirring solution of(1s,4s)-4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanol (748 mg, 3.11mmol) in THF (6 mL) at 0° C. was added sodium hydride (149 mg of a 60%dispersion in mineral oil, 3.73 mmol). The resulting reaction mixturewas stirred at 0° C. for 10 min. Iodoethane (747 μL, 9.34 mmol) was thenadded and the mixture was stirred at room temperature overnight. Furthersodium hydride (75 mg, 1.89 mmol) and iodethane (375 μL, 4.69 mmol) wereadded and the mixture stirred at room temperature overnight. EA (20 mL),water (5 mL) and saturated NH₄Cl solution (10 mL) were added and thelayers were separated. The aqueous was extracted with EA (2×30 mL). Thecombined organic layers were washed with 1 M HCl (10 mL), dried overMgSO₄ and solvents evaporated. The residue was purified by columnchromatography (EA/iso-hexane) to afford 345 mg (39%) of8-((1s,4s)-4-ethoxycyclohexyl)-1,4-dioxaspiro[4.5]decane as a colourlessoil.

(1′s,4′s)-4′-ethoxy-[1,1′-bi(cyclohexan)]-4-one

To a stirring solution of8-((1s,4s)-4-ethoxycyclohexyl)-1,4-dioxaspiro[4.5]decane (345 mg, 1.29mmol) in a mixture of acetone (3 mL) and water (1.5 mL) was added TFA(2.4 mL, 31.2 mmol). The resulting reaction mixture was stirred at roomtemperature for 72 h. Solvents were evaporated and chased off withtoluene. The residue was purified by column chromatography(EA/iso-hexane) to afford 219 mg (74%) of(l's,4′s)-4′-ethoxy-[1,1′-bi(cyclohexan)]-4-one as a pale yellow oil.Molecular formula: C₁₄H₂₄O₂. ¹H NMR (400 MHz, Chloroform-d) δ 3.56-3.49(m, 1H), 3.44 (q, J=7.0 Hz, 2H), 2.43-2.24 (m, 4H), 2.10-2.02 (m, 2H),1.92-1.85 (m, 2H), 1.64-1.54 (m, 1H), 1.51-1.36 (m, 8H), 1.29-1.22 (m,1H), 1.19 (t, J=7.0 Hz, 3H).

Compound 83 was prepared from(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylicacid INT-71 and (l's,4′s)-4′-ethoxy-[1,1′-bi(cyclohexan)]-4-one usingGeneral Procedure 37.

(1r,4r)-4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexan-1-ol

To a stirring suspension of4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone (1.18 g, 4.95 mmol) inMeOH (10 mL) was added sodium borohydride (375 mg, 9.90 mmol) at 0° C.The resulting reaction mixture was stirred for 3 h then quenched withwater (50 mL). The aqueous layer was extracted with DCM (50 mL),acidified with 1 M HCl (10 mL) then reextracted with DCM (20 mL). Theorganic layers were combined and solvents evaporated. The residue wasdissolved in toluene (20 mL), heated to 60° C. then allowed to slowlycool to room temperature. The precipitate was collected by filtrationand washed with hexane to afford 795 mg (67%) of(1r,4r)-4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanol as a white solid.

8-((1r,4r)-4-ethoxycyclohexyl)-1,4-dioxaspiro[4.5]decane

To a stirring solution of(1r,4r)-4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanol (795 mg, 3.31mmol) in THF (12 mL) at 0° C. was added sodium hydride (159 mg of a 60%dispersion in mineral oil, 3.97 mmol). The resulting reaction mixturewas stirred at 0° C. for 10 min. Iodoethane (794 μL, 9.92 mmol) was thenadded and the mixture was stirred at room temperature overnight. Furthersodium hydride (80 mg of a 60% dispersion in mineral oil, 1.99 mmol) andiodethane (400 L, 4.99 mmol) were added. The mixture was stirred at roomtemperature overnight. EA (20 mL), water (5 mL) and saturated NH₄Clsolution (10 mL) were added and the layers were separated. The aqueouswas extracted with EA (2×30 mL). The combined organic layers were washedwith 1 M HCl (10 mL), dried over MgSO₄, filtered and solventsevaporated. The residue was purified by column chromatography(EA/Iso-hexane) to afford 546 mg (58%)8-((1r,4r)-4-ethoxycyclohexyl)-1,4-dioxaspiro[4.5]decane as a clearcolourless oil.

(1′r,4′r)-4′-ethoxy-[1,1′-bi(cyclohexan)]-4-one

To a stirring solution of8-((1r,4r)-4-ethoxycyclohexyl)-1,4-dioxaspiro[4.5]decane (546 mg, 2.03mmol) in a mixture of acetone (4 mL) and water (2 mL) was added TFA (3mL, 38.9 mmol). The resulting reaction mixture was stirred at roomtemperature for 72 h. The reaction mixture was concentrated in vacuo andazeotroped with toluene. The residue was purified by columnchromatography (EA/iso-hexane) to afford 330 mg (69%) of(1′r,4′r)-4′-ethoxy-[1,1′-bi(cyclohexan)]-4-one as a colourless oil.Molecular formula: C₁₄H₂₄O₂. ¹H NMR (400 MHz, Chloroform-d) δ 3.52 (q,J=7.0 Hz, 2H), 3.19-3.13 (m, 1H), 2.41-2.26 (m, 4H), 2.13-2.00 (m, 4H),1.80-1.76 (m, 2H), 1.52-1.40 (m, 3H), 1.27-1.15 (m, 6H), 1.11-0.98 (m,2H).

Compound 84 was prepared from(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylicacid INT-71 and (1′r,4′r)-4′-ethoxy-[1,1′-bi(cyclohexan)]-4-one usingGeneral Procedure 37.

2-methyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexan-1-one

To a stirring solution of LDA (4.62 mL of a 2.0 M solution inTHF/heptane/ethylbenzene, 9.23 mmol) in THF (20 mL) at −78° C. was addedslowly 4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone (2.0 g, 8.39 mmol)in THF (15 mL). The resulting reaction mixture was stirred at −78° C.for 1 h and a solution of iodomethane (0.577 mL, 9.23 mmol) in THF (10mL) was added. The reaction mixture was stirred at −78° C. for 1 h,allowed to warm to room temperature over 2 h and saturated aqueous NH₄Cl(40 mL) was added. The reaction mixture was extracted with Et₂O (100 mL)and the organic layer washed with water (100 mL) and brine (100 mL). Theorganic was then dried over MgSO₄ and solvents evaporated. The residuewas purified by column chromatography (EA/iso-hexane) to afford 1.30 g(58%) of 2-methyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone as anoff-white solid.

(Z)-8-(3-methyl-4-propylidenecyclohexyl)-1,4-dioxaspiro[4.5]decane

To a stirring solution of triphenyl(propyl)phosphonium bromide (1.17 g,3.04 mmol) in THF (10 mL) was added potassium tert-butoxide (341 mg,3.04 mmol). The resulting reaction mixture was stirred at roomtemperature for 1 h then a solution of2-methyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone (590 mg, 2.34mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirredat room temperature for 16 h. The solvents were evaporated. The residuewas treated with Et₂O (50 mL) and stirred for 1 h. The mixture wasfiltered, washed with further Et₂O and solvents evaporated. The residuewas purified by column chromatography (EA/Iso-hexane) to afford 457 mg(70%) of(Z)-8-(3-methyl-4-propylidenecyclohexyl)-1,4-dioxaspiro[4.5]decane as acolourless oil.

8-(3-methyl-4-propylcyclohexyl)-1,4-dioxaspiro[4.5]decane

To a stirring solution of8-(3-methyl-4-propylidenecyclohexyl)-1,4-dioxaspiro[4.5]decane (760 mg,2.73 mmol) in MeOH/THF (1:1, 20 mL) was added 10% Pd/C (76 mg). Theresulting reaction mixture was hydrogenated at 50° C. The mixture wasfiltered and solvents were evaporated to afford 769 mg (99%) of8-(3-methyl-4-propylcyclohexyl)-1,4-dioxaspiro[4.5]decane as acolourless oil.

3′-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-4-one

To a stirring solution of8-(3-methyl-4-propylcyclohexyl)-1,4-dioxaspiro[4.5]decane (769 mg, 2.74mmol) in a mixture of acetone (5 mL) and water (2.5 mL) was added TFA (5mL, 64.9 mmol). The resulting reaction mixture was stirred at roomtemperature overnight. The reaction mixture was added to EA (200 mL) andH₂O (150 mL). The layers were separated. The organic layer was washedwith brine (150 mL) and saturated aqueous NaHCO₃ (150 mL), dried overMgSO₄, filtered and solvents evaporated. The residue was purified bycolumn chromatography (EA/Iso-hexane) to afford 580 mg (89%) of3′-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-4-one as a colourless oil.

3′-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate

To a stirring solution of LDA (795 μL of a 2.0 M solution inTHF/heptane/ethylbenzene, 1.59 mmol) in THF (4 mL) at −78° C. was added3′-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-4-one (289 mg, 1.22 mmol) inTHF (4 mL). The reaction mixture was stirred at −78° C. for 30 min andthen1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(480 mg, 1.35 mmol) in THF (4 mL) was added. The reaction mixture wasstirred at −78° C. for 30 min then at room temperature for 1 h. Asaturated aqueous solution of NaHCO₃ (20 mL) was added to the reactionmixture and the aqueous layer was extracted with EA (2×20 mL). Thecombined organic layers were dried over MgSO₄ and solvents evaporated.The residue was purified by column chromatography (EA/iso-hexane) toafford 270 mg (59%) of3′-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate as a colourless oil.

4,4,5,5-tetramethyl-2-(3′-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolane

To a stirring solution of3′-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate (335 mg, 0.91 mmol) in dioxane (8 mL) wereadded 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (231mg, 0.91 mmol) and potassium acetate (268 mg, 2.73 mmol). The resultingreaction mixture was heated at 40° C. and degassed. PdCl₂(dppf) (13.31mg, 0.02 mmol) was added. The reaction mixture was heated at 90° C. over3 h. The reaction mixture was partitioned between EA (20 mL) and water(20 mL). The aqueous layer was extracted with EA (20 mL). The combinedorganic layers were dried over MgSO₄ and solvents evaporated. Theresidue was purified by column chromatography (EA/iso-hexanes) to afford165 mg (51%) of4,4,5,5-tetramethyl-2-(3′-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolaneas a colourless oil. Molecular formula: C₂₂H₃₉BO₂. ¹H NMR (400 MHz,DMSO-d₆) δ 6.44 (s, 1H), 2.20-2.00 (m, 2H), 1.97-1.85 (m, 1H), 1.83-0.95(m, 27H), 0.93-0.65 (8H).

Compound 85 was prepared from(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylicacid INT-71 and4,4,5,5-tetramethyl-2-(3′-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolaneusing General Procedure 10.

8-(4-(2-methylpropylidene)cyclohexyl)-1, 4-dioxaspiro[4.5]decane

To a stirring solution of isobutyltriphenylphosphonium bromide (5.66 g,14.18 mmol) in THF (45 mL) was added potassium tert-butoxide (1.591 g,14.18 mmol) portionwise. The resulting reaction mixture was stirred atroom temperature for 1 h then4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone (2.6 g, 10.91 mmol) wasadded portionwise. The reaction mixture was stirred at rt for 72 h. Thesolvents were evaporated. The residue was treated with Et₂O (60 mL) andstirred for 1 h. The mixture was filtered, washed with further Et₂O andthe filtrate was evaporated. The residue was purified by columnchromatography (EA/Iso-hexane) to afford 1.63 g (51%) of8-(4-(2-methylpropylidene)cyclohexyl)-1,4-dioxaspiro[4.5]decane as acolourless oil.

8-(4-iso-butylcyclohexyl)-1,4-dioxaspiro[4.5]decane

To a stirring solution of8-(4-(2-methylpropylidene)cyclohexyl)-1,4-dioxaspiro[4.5]decane (1.97 g,6.37 mmol) in IPA (14 mL) were added phenylsilane (0.786 mL, 6.37 mmol)and a solution of tert-butyl hydroperoxide (1.74 mL of a 5-6 M solutionin decane, 9.55 mmol). The resulting mixture was degassed thentris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (0.385 g,0.65 mmol) was added and the mixture was degassed for 30 seconds only.The reaction mixture was stirred for 2 h at room temperature and thesolvent evaporated. The residue was purified by column chromatography(EA/iso-hexanes) to afford 680 mg (38%) of8-(4-iso-butylcyclohexyl)-1,4-dioxaspiro[4.5]decane as a white solid.

4′-iso-butyl-[1,1′-bi(cyclohexan)]-4-one

To a stirring solution of8-(4-iso-butylcyclohexyl)-1,4-dioxaspiro[4.5]decane (630 mg, 2.25 mmol)in a mixture of acetone (4 mL) and water (2 mL) was addedtrifluoroacetic acid (3 mL, 38.9 mmol). The reaction mixture was stirredat room temperature overnight and the solvents were evaporated. Thereaction mixture was added to EA (200 mL) and H₂O (150 mL) and thelayers separated. The organic layer was washed with brine (150 mL) andsaturated aqueous NaHCO₃ (150 mL), dried over MgSO₄, filtered andsolvents evaporated. The residue was purified by column chromatography(EA/Iso-hexane) to afford 399 mg (74%) of4′-iso-butyl-[1,1′-bi(cyclohexan)]-4-one as a white solid.

4′-iso-butyl-[1,1′-bi(cyclohexan)]-3-en-4-yl trifluoromethanesulfonate

To a stirring solution of LDA (495 L of a solution of 2.0 M inTHF/heptane/ethylbenzene, 0.99 mmol) in THF (3 mL) at −78° C. was addeda solution of 4′-iso-butyl-[1,1′-bi(cyclohexan)]-4-one (180 mg, 0.76mmol) in THF (3 mL). The reaction mixture was stirred at −78° C. for 30min and then a solution ofN-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide(359 mg, 0.91 mmol) in THF (3 mL) was added. The reaction mixture wasstirred at −78° C. for 30 min then at room temperature. A saturatedsolution of NaHCO₃ (20 mL) was added to the reaction mixture and theaqueous layer was extracted with EA (2×20 mL). The combined organiclayers were dried over MgSO₄ and solvents evaporated. The residue waspurified by column chromatography (EA/iso-hexane) to afford 163 mg (58%)of 4′-iso-butyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate as a colourless oil.

2-(4′-iso-butyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a stirring solution of 4′-isobutyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate (155 mg, 0.42 mmol) in dioxane (4 mL) wereadded 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (112mg, 0.44 mmol) and potassium acetate (124 mg, 1.26 mmol). The resultingreaction mixture was heated to 40° C. and degassed. PdCl₂(dppf) (6.16mg, 8.41 μmol) was added and the mixture again degassed then heated to90° C. for 3 h. The reaction mixture was partitioned with EA (20 mL) andwater (20 mL). The aqueous layer was extracted once more with EA (20mL). The combined organic layers were dried over MgSO₄, filtered andsolvents evaporated. The residue was purified by column chromatography(EA/iso-hexane) to give 78 mg (51%) of2-(4′-iso-butyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a colourless oil. Molecular formula: C₂₂H₃₉BO₂. ¹H NMR (400 MHz,DMSO-d₆) δ 6.44 (s, 1H), 2.16-2.04 (m, 2H), 1.98-1.86 (m, 1H), 1.79-0.90(m, 27H), 0.88-0.80 (m, 8H).

Compound 86 was prepared from(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylicacid INT-71 and2-(4′-iso-butyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneusing General Procedure 10.

(1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-4-one

To a stirring solution of LDA (5.67 mL of a 2.0 M solution inTHF/heptane/ethylbenzene, 11.33 mmol) in THF (20 mL) at −78° C. wasadded slowly trans-4′-propyl-[1,1′-bi(cyclohexan)]-4-one (2.1 g, 9.44mmol) in THF (15 mL). The reaction mixture was stirred at −78° C. for 1h and a solution of iodomethane (0.709 mL, 11.33 mmol) in THF (10 mL)was added. The reaction mixture was stirred at −78° C. for 1 h, allowedto warm to room temperature over 2 h and saturated aqueous NH₄Cl (40 mL)was added. The reaction mixture was diluted with Et₂O (100 mL) and theorganic layer washed with water (100 mL) and brine (100 mL). The organicwas then dried over MgSO₄, filtered and solvents evaporated. The crudeproduct was purified by column chromatography (EA/Iso-hexane) to afford1.50 g (67%) of(1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-4-one as a paleyellow oil. Molecular formula: C₁₆H₂₈O. ¹H NMR (400 MHz, DMSO-d6) δ2.47-2.35 (m, 1H), 2.25 (app t, J=6.7 Hz, 1H), 2.20-2.06 (m, 1H),2.04-1.9 (m, 1H), 1.97-1.60 (m, 6H), 1.55-1.46 (m, 1H), 1.40-1.23 (m,3H), 1.19-0.80 (m, 14H).

Compound 87 was prepared from(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylic acid INT-71 and(1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-4-one usingGeneral Procedure 37.

8-(4-(methoxymethylene)cyclohexyl)-1,4-dioxaspiro[4.5]decane

To a stirring solution of (methoxymethyl)triphenylphosphonium chloride(3.74 g, 10.91 mmol) in THF (16 mL) was added potassium tert-butoxide(1.224 g, 10.91 mmol) portionwise. The solution was stirred at roomtemperature for 50 min then a solution of4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone (2 g, 8.39 mmol) in THF(16 mL) was added slowly. The reaction mixture was stirred for 3.5 h.The solvent was removed under vacuum. The residue was treated with Et₂O(44 mL) and stirred for 1 h. The mixture was filtered, washed with Et₂O(2×50 mL) and the filtrate was evaporated. The crude product waspurified by column chromatography (EA/Iso-hexane) to afford 1.8 g (76%)of 8-(4-(methoxymethylene)cyclohexyl)-1,4-dioxaspiro[4.5]decane as acolourless oil.

8-((4-(methoxymethyl)cyclohexyl)-1,4-dioxaspiro[4.5]decane

To a stirring solution of8-(4-(methoxymethylene)cyclohexyl)-1,4-dioxaspiro[4.5]decane (1.8 g,6.76 mmol) in EtOH (20 mL) was added 5% Palladium on activated carbon(Johnson and Matthey paste Type 58, 0.132 g, 1.24 mmol). The reactionwas left stirring under 3 bar hydrogen pressure at room temperature for16 h. The mixture was filtered through celite and rinsed with EtOH (150mL). The solvent was evaporated to afford 1.8 g (99%) of8-((1r,4r)-4-(methoxymethyl)cyclohexyl)-1,4-dioxaspiro[4.5]decane as acolourless oil.

4′-(methoxymethyl)-[1,1′-bi(cyclohexan)]-4-one

To a stirring solution of8-(4-(methoxymethyl)cyclohexyl)-1,4-dioxaspiro[4.5]decane (1.8 g, 6.71mmol) in a mixture of acetone (10 mL) and water (5 mL) was added TFA(7.23 mL, 94 mmol). The reaction mixture was stirred at room temperaturefor 2 h. The solvents were evaporated to afford 1.65 g (97%) of4′-(methoxymethyl)-[1,1′-bi(cyclohexan)]-4-one as a colourless oil.

4′-(methoxymethyl)-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate

To a solution of diisopropylamine (1.09 mL, 7.77 mmol) in THF (10 mL)was added n-BuLi (3.11 mL, 7.77 mmol) at −20° C. The mixture was cooledto −78° C. A solution of 4′-(methoxymethyl)-[1,1′-bi(cyclohexan)]-4-one(1.65 g, 6.47 mmol) in THF (10 mL) was added slowly followed by1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(2.43 g, 6.80 mmol). The resultant mixture was stirred at −78° C. for1.75 h then stirred at room temperature for 16 h. A saturated solutionof NaHCO₃ (20 mL) was added to the reaction mixture and the aqueouslayer was extracted with EA (2×30 mL). The organic layers were washedwith brine (30 mL), dried over MgSO₄, filtered and the solventevaporated to afford 2.31 g (100%) of4′-(methoxymethyl)-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate as an orange oil.

2-(4′-(methoxymethyl)-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a stirring solution of4′-(methoxymethyl)-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate (4.52 g, 6.47 mmol) in DMSO (10 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.642 g,6.47 mmol) and potassium acetate (1.904 g, 19.40 mmol). The resultingreaction mixture was warmed to 40° C. and de-gassed. PdCl₂dppf (0.095 g,0.13 mmol) was charged and the mixture was further de-gassed. Thereaction mixture was heated to 100° C. for 8 h then at room temperatureovernight. The mixture was extracted with Et₂O (4×50 mL). The combinedorganics were washed with water (2×50 mL), brine (50 mL), dried overMgSO₄ and evaporated to afford 1.70 g (78%) of2-(4′-(methoxymethyl)-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas an orange oil. Molecular formula: C₂₀H₃₅BO₃. ¹H NMR (400 MHz,Chloroform-d) δ 6.56 (s, 1H), 3.30 (s, 3H), 3.16 (d, J=6.5 Hz, 2H),2.25-2.0 (m, 3H), 1.85-0.81 (m, 26H)

Compound 88 was prepared from(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylicacid INT-71 and2-(4′-(methoxymethyl)-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneusing General Procedure 10.

Trimethyl(((1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)oxy)silane

To a stirring solution of racemic(1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-4-one (500 mg,2.12 mmol) in ACN (20 mL) were added triethylamine (884 μL, 6.35 mmol),chlorotrimethylsilane (403 μL, 3.17 mmol) and sodium iodide (476 mg,3.17 mmol). The reaction mixture was stirred at room temperature for 16h. A saturated solution of NaHCO₃ (50 mL) was added to the reactionmixture and the aqueous layer was extracted with iso-hexane (3×50 mL).The combined organic layers were washed with brine (100 mL), dried overMgSO₄, filtered and solvents evaporated to give 538 mg (74%) of racemictrimethyl(((1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)oxy)silaneas a yellow oil.

(1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethane sulfonate

To a stirring solution of racemictrimethyl(((1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)oxy)silane(484 mg, 1.41 mmol) in THF (6 mL) at 0° C. was added methyllithium (1147L of a 1.6 M solution in Et₂O, 1.84 mmol). After 30 min, TMEDA (1065 μL,7.06 mmol) was added, followed by a solution of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(656 mg, 1.84 mmol) in THF (3 mL). The reaction was stirred at 0° C. for1 h then allowed to warm to room temperature. The reaction mixture wasquenched with saturated aqueous NaHCO₃ (30 mL) and the aqueous layer wasextracted with EA (2×30 mL). The combined organic layers were dried overMgSO₄, filtered and solvents evaporated. The crude product was purifiedby column chromatography (EA/Iso-hexane) to afford 224 mg (43%) ofracemic(1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate as a colourless oil.

4,4,5,5-tetramethyl-2-((1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolane

To a stirring solution of racemic(1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate (260 mg, 0.71 mmol) in dioxane (5 mL) wereadded 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (179mg, 0.71 mmol) and potassium acetate (208 mg, 2.12 mmol). The resultingreaction mixture was heated to 40° C. and degassed. PdCl₂(dppf) (10.33mg, 0.014 mmol) was added and the mixture again degassed then heated to90° C. for 3 h. The reaction mixture was partitioned between EA (20 mL)and water (20 mL). The aqueous layer was extracted once more with EA (20mL). The combined organic layers were dried over MgSO₄ and solventsevaporated. The crude product was purified by column chromatography(EA/iso-hexane) to give 146 mg (57%) of racemic4,4,5,5-tetramethyl-2-((1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolaneas a white solid. Molecular formula: C₂₂H₃₉BO₂. ¹H NMR (400 MHz,Chloroform-d) δ 2.28-2.19 (m, 1H), 2.05-1.95 (m, 2H), 1.90 (s, 3H),1.83-1.68 (m, 6H), 1.35-1.21 (m, 14H), 1.16-0.82 (m, 13H).

Compound 89 was prepared from(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylicacid INT-71 and4,4,5,5-tetramethyl-2-((1RS,1′s,4′RS)-3-methyl-4′-propyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolaneusing General Procedure 10.

1-(4-(benzyloxy)phenyl)-4,4-dimethylcyclohexanol

To a stirring suspension of magnesium (1.847 g, 76 mmol) in THF (15 mL)at ˜60° C. was added iodine (˜20 mg). After 30 min, a solution of1-(benzyloxy)-4-bromobenzene (10 g, 38.0 mmol) in THF (45 mL) was addedslowly to maintain borderline reflux (˜2 h addition). The mixture wasstirred at −60° C. for a further 2 h then allowed to cool to roomtemperature then further cooled to −10° C. whereupon a solution of4,4-dimethylcyclohexanone (8.5 mL, 34.5 mmol) in THF (15 mL) was addedto maintain internal temperature between −5° C. and −10° C. After afurther 1 h, the mixture was quenched with NH₄Cl (100 mL) and extractedwith diethylether (2×100 mL). The combined organics were dried overMgSO₄, filtered and evaporated to afford 10.7 g (100%) of1-(4-(benzyloxy)phenyl)-4,4-dimethylcyclohexanol as a yellow oil.LCMS-ESI (m/z) calculated for C₂₁H₂₆O₂: 310.2; found 293.2 [M+H-H₂O]⁺,t_(R)=2.90 min (Method 11).

4′-(benzyloxy)-4,4-dimethyl-2,3,4,5-tetrahydro-1,1′-biphenyl

To a stirring solution of1-(4-(benzyloxy)phenyl)-4,4-dimethylcyclohexanol (10.7 g, 34.5 mmol) inMeOH (135 mL) was added concentrated HCl (15 mL). The resulting reactionmixture was heated to 50° C. for 1 h. The reaction mixture was allowedto cool and the product was collected by filtration, washed with MeOH toafford 4.32 g (39%) of4′-(benzyloxy)-4,4-dimethyl-2,3,4,5-tetrahydro-1,1′-biphenyl as a yellowsolid. LCMS-ESI (m/z) no ionisation, t_(R)=3.26 min (Method 11).

4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-4-one

To a stirring solution of4′-(benzyloxy)-4,4-dimethyl-2,3,4,5-tetrahydro-1,1′-biphenyl (4.32 g,14.77 mmol) in xylene (55 mL) was added 5% palladium on alumina (PowderType 325; 1 g). The resulting reaction mixture was purged with nitrogenand hydrogen gas then stirred at 100° C. under hydrogen (5 bars)overnight. The reaction mixture was filtered through a glass microfibrefilter, washed with EtOH. The solvents were evaporated. The crudeproduct was purified by column chromatography (EA/iso-hexane) to afford1.55 g (50%) of 4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-4-one as acolourless oil.

4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl trifluoromethanesulfonate

To a stirring solution of diisopropylamine (1.251 mL, 8.93 mmol) in THF(35 mL) was added n-BuLi (3.57 mL, 8.93 mmol) at −20° C. The mixture wascooled to −78° C. 4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-4-one (1.55 g,7.44 mmol) in THF (35 mL) was added slowly followed by1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(2.79 g, 7.81 mmol). The resultant mixture was stirred at −78° C. for 1h then stirred at room temperature for 16 h. A saturated solution ofNaHCO₃ (80 mL) was added to the reaction mixture and the aqueous layerwas extracted with EA (2×120 mL). The organic layers were combined,dried over MgSO₄ and the solvents evaporated. The crude product waspurified by column chromatography (EA/iso-hexane) to afford 807 mg (32%)of 4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate as a colorless oil.

2-(4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a stirring solution of 4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate (807 mg, 2.37 mmol) in dioxane (15 mL) wereadded 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (602mg, 2.37 mmol) and potassium acetate (698 mg, 7.11 mmol). The resultingreactin mixture was heated to 40° C. and degassed. PdCl₂(dppf) (34.7 mg,0.047 mmol) was added and the mixture again degassed then heated to 90°C. for 4 h. The reaction mixture was partitioned between EA (20 mL) andwater (20 mL). The aqueous layer was extracted with EA (3×20 mL). Thecombined organic layers were dried over MgSO4 and solvents evaporated.The crude product was purified by column chromatography (EA/iso-hexane)to afford 450 mg (57%) of2-(4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a yellow oil that crystallised upon standing. Molecular formula:C₂₀H₃₅BO₂. ¹H NMR (400 MHz, Chloroform-d) δ 6.57 (s, 1H), 2.28-1.98 (m,3H), 1.89-1.73 (m, 2H), 1.59-1.45 (m, 3H), 1.41-1.30 (m, 3H), 1.28-0.95(m, 17H), 0.88 (s, 3H), 0.85 (s, 3H).

Compound 90 was prepared from(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylicacid INT-71 and2-(4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneusing General Procedure 10.

(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-ethylthiophene-2-carboxamido)propanoicacid

Prepared using General Procedure 8: To a stirring solution of tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-ethylthiophene-2-carboxamido)propanoate(0.8 g, 1.5 mmol) in DCM (10 mL) was treated with TFA (4 mL). Thereaction mixture was stirred at room temperature for 16 hours tocomplete. The solvent was evaporated and then co-evaporated with toluene(3×20 mL) to remove trace TFA. The residue was suspended in acetonitrile(10 mL) and the solid formed was filtered. The compound was dried undervacuum overnight to afford 0.46 g (68%) of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-ethylthiophene-2-carboxamido)propanoicacid as half-white powder. LCMS-ESI (m/z) calculated for C₂₀H₁₈BrN₃O₃S:460.3; found 462.3 [M+2]⁺, t_(R)=2.76 min (Method 18).

tert-Butyl(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-ethylthiophene-2-carboxamido)propanoyl)azetidine-3-carboxylate(INT 73)

Prepared using General Procedure 7: To a stirred solution of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-ethylthiophene-2-carboxamido)propanoicacid (0.43 g, 0.93 mmol) in DMF (5 mL) at 0° C. was added DIPEA (0.6 g,4.6 mmol) followed by tert-butyl azetidine-3-carboxylate hydrochloride(0.22 g, 1.1 mmol). To the mixture was added HATU (0.88 g, 2.33 mmol).The reaction was allowed to stir at 0° C. for 2 h and then allowed towarm to RT for 16 h. Then the reaction mixture was diluted withsaturated sodium bicarbonate solution (5 mL), water (5 mL) and EA (10mL). The layers were separated and the aqueous layer was extracted withEA (2×10 mL). The combined organic layers were washed with 1Nhydrochloric acid, water, brine and then dried over MgSO₄ andconcentrated. The crude product was purified by column chromatography(0-40% EA/Hexanes) to afford 0.43 g (76%) of tert-butyl(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-ethylthiophene-2-carboxamido)propanoyl) azetidine-3-carboxylate INT 73. LCMS-ESI (m/z) calculated forC₂₈H₃₁BrN₄O₄S: 599.5; found 601.3 [M+2]⁺, t_(R)=4.22 min (Method 25).

(1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate

To a stirring solution of diisopropylamine (17.3 mL, 124 mmol) in THF(350 mL) at 0° C. was added butyllithium (41.9 mL of a 2.7 M solution inhexanes, 113 mmol). After 30 min, the mixture was cooled to −78° C. andtreated with a solution of(1′r,4′r)-4′-methyl-[1,1′-bi(cyclohexan)]-4-one (20 g, 103 mmol) in THF(100 mL) added over 1 h. After 30 min, a solution of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(44.1 g, 124 mmol) in THF (180 mL) was added over 1 h. The resultantmixture was allowed to warm slowly to RT. The reaction mixture wascarefully quenched with ice/NaHCO₃ (200/250 mL) and extracted with EA(2×300 mL). The combined organics were dried over MgSO₄ and solventsevaporated. Column chromatography (EA/iso-hexanes) gave 30.7 g (91%) ofracemic (1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate.

4,4,5,5-tetramethyl-2-((1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolane

To a stirring solution of racemic(1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate (30.7 g, 94 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (26.3 g, 103mmol) in dioxane (400 mL) at 40° C. was added potassium acetate (27.7 g,282 mmol) and the mixture degassed. PdCl₂(dppf) (1.377 g, 1.881 mmol)was added and heated to 100° C. for 4 h. The mixture was allowed to coolthen quenched with water (500 mL) and extracted with EA (3×700 mL). Thecombined organic extracts were dried over MgSO₄ and solvents evaporated.Column chromatography (EA/iso-hexanes) gave 12.1 g (42%) of racemic4,4,5,5-tetramethyl-2-((1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolane.Molecular formula: C₁₉H₃₃BO₂. ¹H NMR (400 MHz, Chloroform-d) δ 6.60-6.57(m, 1H), 2.36-1.96 (m, 3H), 1.95-1.67 (m, 6H), 1.40-0.78 (m, 23H).

Compound 91 was prepared from INT-73 using General Procedure 10 withracemic4,4,5,5-tetramethyl-2-((1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolanefollowed by General Procedure 8.

Compound 92 was prepared from INT-73 using General Procedure 10 with2-(4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand then General Procedure 8.

(Z)—N′-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-4-ylidene)-4-methylbenzenesulfonohydrazide

A stirring mixture of (1′r,4′r)-4′-ethyl-[1,1′-bi(cyclohexan)]-4-one(100 g, 470 mmol) and 4-methylbenzenesulfonohydrazide (90 g, 470 mmol)in EtOH (1700 mL) was heated at 100° C. for 3 h. The reaction mixturewas allowed to cool down to room temperature. The precipitate wascollected by filtration, washed with cold EtOH (100 mL) and dried in thevacuum oven at 50° C. to afford 170 g (94%) of racemic(Z)—N′-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-4-ylidene)-4-methylbenzenesulfonohydrazideas a white solid.

2-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A stirring mixture of racemic(Z)—N′-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-4-ylidene)-4-methylbenzenesulfonohydrazide(47 g, 125 mmol) and N1,N1,N2,N2-tetramethylethane-1,2-diamine (381 mL,2496 mmol) in isohexanes (400 mL) was cooled to −78° C. and then treatedafter 15 min with n-BuLi (200 mL of a 2.5 M solution, 499 mmol). After20 min, the cooling bath was removed. After a further 2 h stirring, themixture was cooled to −78° C. and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105 mL, 499 mmol)was added slowly. The reaction mixture was stirred at −78° C. and thenleft to warm up to room temperature overnight. The reaction mixture wasquenched with NH₄Cl (400 mL). The reaction mixture was partitionedbetween water (2.5 L) and Et₂O (1.5 L). The organic layer was dried overMgSO₄, filtered and solvents evaporated. The residue was treated withMeOH (200 mL) and cooled down using an ice-water bath. The solid formedwas collected by filtration to afford 23.78 g (59%) of racemic2-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas an off-white solid. Molecular formula: C₂₀H₃₅BO₂. ¹H NMR (400 MHz,DMSO-d₆) δ 6.43 (s, 1H), 2.17-2.04 (m, 2H), 1.98-1.86 (m, 1H), 1.84-1.65(m, 6H), 1.31-0.77 (m, 25H).

Compound 93 was prepared from INT-73 using General Procedure 10 withracemic2-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefollowed by General Procedure 8.

tert-Butyl1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate

Prepared using General Procedure 10: To a stirring solution oftert-butyl(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoyl) azetidine-3-carboxylate (1.1 g, 1.9 mmol) and racemic2-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.7 g, 2.2 mmol) in 3:1 dioxanes: H₂O (14 mL) was added sodiumcarbonate, decahydrate (1.1 g, 3.7 mmol). The mixture was degassed usingnitrogen bubbling and then PdCl₂(dppf) (0.14 g, 0.2 mmol) was added andthe mixture was heated at 70° C. After 3 h, the reaction mixture wasdiluted with DCM and washed with brine. The organic layer was dried(Na₂SO₄) and purified by column chromatography (EA/hex) to provide 1.3 g(99%) of a mixture of diastereomers tert-butyl1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate.LCMS-ESI (m/z) calculated for C₄₃H₅₄N₄O₅: 706.9; found 707.4 [M+H]⁺,t_(R)=5.3 min (Method 25).

tert-butyl1-((S)-2-amino-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(INT-74)

Prepared using General Procedure 18. To a stirring solution of mixtureof diastereomers of tert-butyl1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate(100 mg, 0.14 mmol) in EA (6 mL) was added Pd/C (10 mg, 0.01 mmol) andthe reaction was flushed with hydrogen gas three times. The reactionmixture was stirred under an atmosphere of hydrogen for 36 hours, thenconcentrated, dissolved in MeOH, filtered through Celite, and againconcentrated to give 76 mg (95%) of a mixture of diastereomerstert-butyl1-((S)-2-amino-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylateINT-74. LCMS-ESI (m/z) calculated for C₃₅H₄₈N₄O₃: 572.8 found 573.4[M+H]+, t_(R)=5.02 min (Method 25).

Compounds 94-104 were prepared from INT-74 using General Procedure 7with the respective carboxylic acid followed by General Procedure 8.

Compounds 105-108 were prepared from Compound 119 using GeneralProcedure 7 with the respective amine followed by General Procedure 8.

(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoicacid

Prepared using General Procedure 8: To a stirring solution of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoateINT-7 (12 g, 23.42 mmol) in DCM (210 mL) was added TFA (150 mL). After 3h, the mixture was diluted with DCM (100 mL) and poured onto ice water(500 mL). The organic phase was separated, washed with water (2×100 mL),dried over MgSO₄ and solvents evaporated to give 10.7 g (100%) of(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoicacid (12.16 g, 23.45 mmol, 100% yield). LCMS-ESI (m/z) calculated forC₂₁H₁₈BrN₃O₄: 455.1; found 456.1 [M+H]⁺, t_(R)=6.08 min (Method 10).

(S)-benzyl(3-(4-(5-bromopyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)carbamate

Prepared using General Procedure 7: To a stirring solution of(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoicacid (12.16 g, 23.45 mmol) in DCM (250 mL) was added methanesulfonamide(22.31 g, 235 mmol), DMAP (5.73 g, 46.9 mmol) and DIEA (20.48 mL, 117mmol) followed by EDC (6.29 g, 32.8 mmol). The reaction mixture wasallowed to stir at room temperature for 3 days then quenched intoice-water (200 mL), acidified with 1 M HCl (250 mL) and extracted withDCM (400 mL). The organic layer was washed with 0.1 M HCl (3×200 mL),dried over MgSO₄, filtered and solvents evaporated to afford 10.5 g(84%) of (S)-benzyl(3-(4-(5-bromopyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)carbamate. LCMS-ESI (m/z) calculated for C₂₂H₂₁BrN₄O₅S: 532.0; found533.0 [M+H]⁺, t_(R)=2.34 min (Method 11).

(S)-2-amino-3-(4-(5-bromopyrimidin-2-yl)phenyl)-N-(methylsulfonyl)propanamide

To stirring hydrogen bromide (107 mL of a 33% solution in AcOH, 591mmol) was added (S)-benzyl(3-(4-(5-bromopyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)carbamate(10.5 g, 19.70 mmol). After 2 h, diethyl ether (100 mL) was added andthe precipitate collected by filtration, washing with iso-hexanes (4×50mL) to afford 9.5 g (100%) of(S)-2-amino-3-(4-(5-bromopyrimidin-2-yl)phenyl)-N-(methylsulfonyl)propanamideas the HBr salt. LCMS-ESI (m/z) calculated for C₁₄H₁₅BrN₄O₃S: 398.0;found 399.1 [M+H]⁺, t_(R)=1.21 min (Method 11).

(S)—N-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)-5-(tert-butyl)thiophene-2-carboxamide

Prepared using General Procedure 7: To a stirring solution of5-(tert-butyl)thiophene-2-carboxylic acid (4.56 g, 23.53 mmol) and DIEA(21.72 mL, 118 mmol) in DMF (95 mL) was added portionwise HATU (8.95 g,23.53 mmol). After 30 min, the yellow solution was added to a stirringsolution of(S)-2-amino-3-(4-(5-bromopyrimidin-2-yl)phenyl)-N-(methylsulfonyl)propanamide,HBr (9.5 g, 19.61 mmol) in DMF (190 mL). After 1.5 h, ice-water (190 mL)was added. After 10 min acetic acid (8.97 mL, 157 mmol) was added. Aftera further 10 min, more water added (300 mL). The mixture was allowed tostir at room temperature for 15 min. The precipitate was collected byfiltration washed successively with water (2×100 mL), iso-hexanes (2×100mL), water (2×100 mL) and iso-hexanes (2×100 mL) to give 11.1 g (100%)of(S)—N-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)-5-(tert-butyl)thiophene-2-carboxamide. LCMS-ESI (m/z) calculated for C₂₃H₂₅BrN₄O₄S₂:564.1; found 565.1 [M+H]⁺, t_(R)=2.58 min (Method 11).

5-(tert-butyl)-N—((S)-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)thiophene-2-carboxamide(Compound 109)

Prepared using General Procedure 10: To a stirring solution of(S)—N-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-1-(methylsulfonamido)1-oxopropan-2-yl)-5-(tert-butyl)thiophene-2-carboxamide (5.25 g, 9.28 mmol) and racemic2-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3.55 g, 11.14 mmol) in dioxane (200 mL) was added sodiumhydrogencarbonate (25.8 mL of a 0.9 M aqueous solution, 23.21 mmol). Themixture was warmed to 40° C., de-gassed, then treated with PdCl₂dppf(0.303 g, 0.371 mmol) then heated under reflux for 6 h. The mixture wasallowed to cool then poured onto 1 M HCl (200 mL) and extracted with EA(3×200 mL). The combined organic extracts were washed with brine (200mL), dried over MgSO₄, filtered and solvents evaporated. The residue waspurified by column chromatography (AcOH/EA/DCM/iso-hexanes) thenre-slurried from ACN. The residue was further purified by reverse phasecolumn chromatography (RP Flash C18, ACN/water/formic acid) to afford4.25 g (68%) of a mixture of diastereomers5-(tert-butyl)-N—((S)-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)thiophene-2-carboxamide.LCMS-ESI (m/z) calculated for C₃₇H₄₈N₄O₄S₂: 676.3; found 677.3 [M+H]⁺,t_(R)=3.39 min (Method 11). Chiral analysis (Chiral Method 1)showed >95% single peak. ¹H NMR (400 MHz, DMSO-d₆) δ 12.18 (s, 1H), 8.91(s, 2H), 8.70-8.68 (m, 1H), 8.45-8.19 (m, 2H), 7.67 (d, J=3.9 Hz, 1H),7.51 (d, J=8.3 Hz, 2H), 6.93 (d, J=3.8 Hz, 1H), 6.49-6.34 (m, 1H),4.75-4.69 (m, 1H), 3.24-3.17 (m, 4H), 3.06 (dd, J=13.6, 10.8 Hz, 1H),2.49-2.19 (m, 3H), 2.00-1.92 (m, 2H), 1.87-1.70 (m, 4H), 1.38-1.29 (m,11H), 1.23-0.95 (m, 6H), 0.91-0.82 (m, 5H).

(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylic acid

A solution of sulfuric acid (119 mL, 2228 mmol) in acetic acid (300 mL)and water (300 mL) was prepared and allowed to cool to room temperature.This was added to a stirred solution of methyl1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylateINT-35 (44.5 g, 74.3 mmol) in dioxane (500 mL). After 16 h, the mixturewas poured into ice water (1 L) and extracted with DCM (2×1 L). Thecombined organic extracts were washed with water (2×1 L), dried overMgSO₄ and solvents evaporated. Column chromatography(AcOH/EA/DCM/iso-hexanes) gave clean product and mixed fractions. Thesemixed fractions were further purified by column chromatography(AcOH/EA/DCM/iso-hexanes) and the clean products combined andre-slurried from ACN to afford 26.3 g (60%) of(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylic acid. LCMS-ESI (m/z) calculated forC₂₇H₂₉BrN₄O₄S: 584.1; found 585.1 [M+H]⁺, t_(R)=2.48 min (Method 11).

(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylicacid (Compound 110)

Prepared using General Procedure 10: To a stirring solution of(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl) pyrrolidine-3-carboxylic acid (5.7 g, 9.74 mmol) and racemic2-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3.41 g, 10.71 mmol) in dioxane (150 mL), was added NaHCO₃ (32.5 mL of a0.9 M aqueous solution, 29.2 mmol) and the mixture degassed. PdCl₂(dppf)(0.356 g, 0.487 mmol) was added and the mixture heated under reflux.After 3 h, the mixture was allowed to cool then poured onto a mixture ofice-water (75 mL) and 1 M HCl (125 mL). The precipitate was collected byfiltration, washing with water (50 mL). The solid was re-slurried fromACN (150 mL) then purified by column chromatography(AcOH/THF/DCM/iso-hexanes). The product was again re-slurried from ACN(200 mL) to afford 4.74 g (70%) of a mixture of diastereomers(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-((1RS,1′r,4′RS)-4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylicacid. LCMS-ESI (m/z) calculated for C₄₁H₅₂N₄O₄S: 696.4; no m/z observed,t_(R)=11.05 min (Method 10). Chiral analysis (Chiral Method 1)showed >95% single peak. ¹H NMR (400 MHz, DMSO-d₆) δ 12.53 (s, 1H), 8.91(d, J=0.8 Hz, 2H), 8.78 (t, J=8.2 Hz, 1H), 8.27 (d, J=8.0 Hz, 2H), 7.73(d, J=3.9 Hz, 1H), 7.44 (dd, J=8.5, 2.3 Hz, 2H), 6.92 (dd, J=3.9, 0.9Hz, 1H), 6.51-6.37 (m, 1H), 5.00-4.73 (m, 1H), 3.88-3.83 (m, 0.5H),3.72-3.66 (m, 0.5H), 3.62-3.36 (m, 2H), 3.17-2.87 (m, 3H), 2.49-2.19 (m,3H), 2.13-1.69 (m, 8H), 1.36-1.32 (m, 11H), 1.23-0.67 (m, 12H).

Compounds 111-114 and 116 were prepared from Compound 123 using GeneralProcedure 7 using the respective amine followed by General Procedure 8.

Compound 115 was prepared from Compound 123 using General Procedure 7.

tert-butyl (tert-butoxycarbonyl)-L-tyrosinate

To a stirring solution of sodium bicarbonate (37.4 g, 445 mmol) in water(1 L) was added (S)-tert-butyl 2-amino-3-(4-hydroxyphenyl)propanoate (96g, 405 mmol) and acetone (850 mL). A solution of di-tert-butyldicarbonate (97 g, 445 mmol) in acetone (220 mL) was then added slowlyover 2 h. After a further 16 h, the mixture was treated with water (1.7L) then treated with a solution of AcOH (30 mL) in water (300 mL) addedslowly. The mixture was extracted with EA (1 L) and the organics driedover Na₂SO₄ and partially concentrated. The residue was re-slurried withiso-hexanes (1 L). The precipitate was collected by filtration, washingwith iso-hexanes (100 mL) to afford 128.4 g (94%) of tert-butyl(tert-butoxycarbonyl)-L-tyrosinate. LCMS-ESI (m/z) calculated forC₁₈H₂₇NO₅: 337.2; found 360.2 [M+Na]⁺, t_(R)=5.93 min (Method 10).

tert-butyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate

To a stirred solution of tert-butyl (tert-butoxycarbonyl)-L-tyrosinate(145 g, 429 mmol) in DCM (1.5 L) was added DIEA (95 mL, 514 mmol) then1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(7.66 g, 21.5 mmol). After 16 h, additional1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(7.66 g, 21.5 mmol) was added. After a further 3 h, additional1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(153.11 g, 429 mmol) was added. After a further 20 h, the mixture waswashed successively with a solution of citric acid monohydrate (105 g,500 mmol) in water (1.5 L) then saturated aqueous sodium bicarbonate (1L). The organics were dried over Na₂SO₄ and solvents evaporated toafford tert-butyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate,overweight with phenyltriflimide and used crude for the next step.LCMS-ESI (m/z) calculated for C₁₉H₂₆F₃NO₇S: 469.1; found 492.2 [M+Na]⁺,t_(R)=2.87 min (Method 11).

tert-Butyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

A stirred mixture of tert-butyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate(crude from previous step, assumed 429 mmol), potassium acetate (126 g,1287 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (109 g, 429mmol) in DMSO (750 mL) was warmed to 40° C. and de-gassed. The PdCl₂dppf(6.28 g, 8.58 mmol) was charged, the mixture again de-gassed, thenheated to 100° C. After 2.5 h, the mixture was allowed to cool thenextracted with Et₂O (3×750 mL). The combined organics were washed withwater (2×600 mL then 1×1 L), dried over Na₂SO₄ and solvents evaporatedto afford 188.9 g (98%) of tert-butyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) propanoate as a brown solid used directly for the next step.LCMS-ESI (m/z) calculated for C₂₄H₃₈BNO₆: 447.3; found 470.3 [M+Na]⁺,t_(R)=2.99 min (Method 11). ¹H NMR (400 MHz, DMSO-d₆) δ 7.63-7.55 (m,2H), 7.25 (d, J=7.8 Hz, 2H), 7.15 (d, J=8.1 Hz, 1H), 4.01 (ddd, J=9.7,8.1, 5.5 Hz, 1H), 3.05-2.78 (m, 2H), 1.36 (s, 9H), 1.34 (s, 9H), 1.29(s, 12H).

tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate

A stirred solution of sodium carbonate decahydrate (242 g, 844 mmol) inwater (0.9 L) was treated with (S)-tert-butyl2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(188.9 g, 422 mmol) and 5-bromo-2-iodopyrimidine (120 g, 422 mmol) indioxane (1.8 L) and the resulting mixture warmed to 40° C. and de-gassedby bubbling with N₂. The PdCl₂dppf (6.18 g, 8.44 mmol) was charged andthe mixture heated under gentle reflux for 6 h. The mixture was allowedto cool to 40° C. then treated with water (1.8 L) and cooled to 20° C.The precipitate was collected by filtration. The reaction vessel waswashed out with acetone (250 mL) and this solution treated with water(300 mL) to afford a second crop of precipitate that was combined withthe bulk material. The precipitated solid was washed successively withwater (2×500 mL) and iso-hexanes (2×500 mL). This was then slurried inEtOH (550 mL) and heated under reflux for 30 min. The suspension wascooled to 20° C. and the precipitate collected by filtration, washingwith EtOH (200 mL) to afford 146.8 g (73%) of tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl) phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as a fine beige powder. LCMS-ESI (m/z) calculated forC₂₂H₂₈BrN₃O₄: 477.1; found 500.1 [M+Na]⁺, t_(R)=2.18 min (Method 6). ¹HNMR (400 MHz, DMSO-d₆) δ 9.00 (s, 2H), 8.25-8.12 (m, 2H), 7.34 (d, J=8.2Hz, 2H), 7.18 (d, J=8.0 Hz, 1H) 4.05-3.94 (m, 1H), 3.06-2.73 (m, 2H),1.28 (m, 18H).

tert-butyl (S)-2-amino-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate(INT-79)

To a stirred solution of (S)-tert-butyl3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate(146.77 g, 307 mmol) in DCM (500 mL) was added hydrogen chloride (614 mLof a 5-6 N solution in IPA, ˜3.1 mol). After 1 h, the product wascollected by filtration, washing with IPA (100 mL) then ether (2×100 mL)to afford 122.3 g (96%) of tert-butyl(S)-2-amino-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate (hydrochloridesalt). LCMS-ESI (m/z) calculated for C₁₇H₂₀BrN₃O₂*HCl: 377.1; found378.1 [M+H]⁺, t_(R)=2.99 min (Method 10). ¹H NMR (400 MHz, DMSO-d₆) δ9.09 (s, 2H), 8.61 (br s, 3H), 8.39-8.25 (m, 2H), 7.57-7.37 (m, 2H),4.21 (br s, 1H), 3.42-3.19 (m, 1H), 3.09 (dd, J=14.0, 8.4 Hz, 1H), 1.31(s, 9H).

The product was dissolved in CHCl₃/MeOH and washed with saturatedaqueous sodium bicarbonate to afford the free base.

Compounds 117 and 118 were prepared from (S)-tert-butyl2-amino-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate INT-79 usingGeneral Procedures 7, 8, 7, 4 and 10 sequentially.

Compound 119 was prepared from INT-17 using General Procedures 10 then8.

8-cyclohexyl-1,4-dioxaspiro[4.5]decane

To a stirring solution of 4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone(1 g, 4.20 mmol) in diethylene glycol (15 mL) were added hydrazine (3.92mL, 62.9 mmol) and potassium hydroxide (2.354 g, 42.0 mmol). Thereaction mixture was heated up to 160° C. for 16 h then up to 210° C.for 1 h. The reaction mixture was cooled down to room temperature andquenched with a solution of NH₄Cl (120 mL). The aqueous layer wasextracted with EA (3×80 mL). The combined organic layers were dried overMgSO₄, filtered and solvents evaporated. The crude product was purifiedby column chromatography (EA/Iso-hexane) to afford 728 mg (77%) of8-cyclohexyl-1,4-dioxaspiro[4.5]decane as a white solid.

[1,1′-bi(cyclohexan)]-4-one

To a stirring solution of 8-cyclohexyl-1,4-dioxaspiro[4.5]decane (724mg, 3.23 mmol) in a mixture of acetone (4 mL) and water (2 mL) was addedtrifluoroacetic acid (3 mL, 38.9 mmol). The reaction mixture was stirredat room temperature for 4 h. The solvents were evaporated. The crudeproduct was purified by column chromatography (EA/Iso-hexane) to afford582 mg (100%) of [1,1′-bi(cyclohexan)]-4-one as a colourless oil.

[1,1′-bi(cyclohexan)]-3-en-4-yl trifluoromethanesulfonate

To a stirring solution of [1,1′-bi(cyclohexan)]-4-one (622 mg, 3.45mmol) in THF (10 mL) at −78° C. was added1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1233 mg, 3.45 mmol) and lithium bis (trimethylsilyl)amide (3.8 mL of a1 M solution in THF, 3.80 mmol). The solution was stirred for 2 h at−78° C. then stirred at room temperature for 72 h. A saturated solutionof NaHCO₃ (20 mL) was added to the reaction mixture and the aqueouslayer was extracted with EA (3×30 mL). The organic layers were driedover MgSO₄ and the solvents evaporated. The crude product was purifiedby column chromatography (EA/iso-hexane) to afford 519 mg (48%) of[1,1′-bi(cyclohexan)]-3-en-4-yl trifluoromethanesulfonate as a colorlessoil.

2-([1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A stirring solution of [1,1′-bi(cyclohexan)]-3-en-4-yltrifluoromethanesulfonate (519 mg, 1.66 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (422 mg,1.66 mmol) and potassium acetate (489 mg, 4.98 mmol) in dioxane (10 mL)was heated to 40° C. and degassed. PdCl₂(dppf) (24.32 mg, 0.033 mmol)was added and the mixture again degassed then heated to 90° C. for 3 h.The reaction mixture was partitioned between EA (20 mL) and water (20mL). The aqueous layer was extracted once more with EA (20 mL). Thecombined organic layers were dried over MgSO4, filtered and solventsevaporated. The crude product was purified by column chromatography(EA/iso-hexane) to afford 100 mg (20%) of2-([1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a colourless oil. Molecular formula: C₁₈H₃₁BO₂. ¹H NMR (400 MHz,DMSO-d₆) δ 5.70 (m, 1H), 1.43-1.27 (m, 2H), 1.32-1.27 (m, 1H), 1.08-0.81(m, 7H), 0.53-0.12 (m, 20H).

Compound 120 was prepared from (S)-tert-butyl3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateINT-17 using General Procedure 8 followed by General Procedure 10 using2-([1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

8-(4-propylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol

To a stirring solution of 1,4-dioxaspiro[4.5]decan-8-one (1 g, 6.40mmol) in THF (10 mL) was added (4-propylphenyl)magnesium bromide (23 mLof a 0.5 M solution in THF, 11.50 mmol). The reaction heated underreflux for 5 h. The mixture was allowed to cool then quenched intosaturated aqueous NH₄Cl and extracted with EA (2×40 mL). The combinedorganic extracts were dried over MgSO₄ and solvents evaporated. Columnchromatography (EA/iso-hexanes) gave 1.38 g 77% of8-(4-propylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol as a white solid.

8-(4-propylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene

To a stirring mixture of8-(4-propylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol (1.38 g, 4.99 mmol) inTHF (24 mL) was added Burgess reagent (2.38 g, 9.99 mmol). The mixturewas heated at 50° C. for 3 h. The solvent was evaporated and thereaction mixture partitioned between water (30 mL) and DCM (50 mL).Solvents were evaporated and the residue purified by columnchromatography (EA/iso-hexanes) to afford 1.21 g (93%) of8-(4-propylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene (1.21 g, 4.64 mmol, 93%yield) as a colourless oil.

8-(4-propylphenyl)-1,4-dioxaspiro[4.5]decane

To a stirring solution of8-(4-propylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene (1.208 g, 4.68 mmol) inEtOH (30 mL) was added Palladium on carbon (10% Johnson and MattheyPaste Type 39, 200 mg) and the mixture hydrogenated under 5 bar for 4 h.The mixture was filtered through Celite and solvents evaporated toafford 1.18 g (96%) of 8-(4-propylphenyl)-1,4-dioxaspiro[4.5]decane.

4-(4-propylphenyl)cyclohexanone

To a stirring solution of 8-(4-propylphenyl)-1,4-dioxaspiro[4.5]decane(1.12 g, 4.30 mmol) in acetone (6 mL) and water (3 mL) was added TFA(4.5 mL, 58.4 mmol). After 16 h, solvents were evaporated and theresidue purified by column chromatography (EA/iso-hexanes) to affordproduct and recovered starting material. The recovered starting materialwas re-submitted to the reaction conditions above and products combinedto afford 678 mg (69%) of 4-(4-propylphenyl)cyclohexanone.

4′-propyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yltrifluoromethanesulfonate

To a stirring solution of diisopropylamine (0.53 mL, 3.76 mmol) in THF(15 mL) at −20° C. was added butyllithium (1.5 mL of a 2.5 M solution inhexanes, 3.76 mmol). The mixture was cooled to −78° C. whereupon asolution of 4-(4-propylphenyl)cyclohexanone (678 mg, 3.13 mmol) in THF(15 mL) was added slowly followed by1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1176 mg, 3.29 mmol). After 1 h, the mixture was allowed to warm to roomtemperature. The mixture was quenched into NaHCO₃ (40 mL) and extractedwith EA (3×50 mL). The combined organic extracts were dried over MgSO₄and solvents evaporated. Column chromatography (EA/iso-hexanes) gave 506mg (46%) of 4′-propyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yltrifluoromethanesulfonate.

4,4,5,5-tetramethyl-2-(4′-propyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yl)-1,3,2-dioxaborolane

To a stirring solution of4′-propyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yltrifluoromethanesulfonate (506 mg, 1.452 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (369 mg,1.452 mmol) in dioxane (8 mL) was added potassium acetate (428 mg, 4.36mmol). The mixture was heated to 40° C. and degassed then treated withPdCl₂(dppf) (21 mg, 0.029 mmol) and heated to 90° C. for 4 h. Themixture was allowed to cool then diluted with water (20 mL) andextracted with EA (4×20 mL). The combined organic extracts were driedover MgSO₄ and solvents evaporated. Column chromatography gave 146 mg(31%) of4,4,5,5-tetramethyl-2-(4′-propyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yl)-1,3,2-dioxaborolane.Molecular formula: C₂₁H₃₁BO₂. ¹H NMR (400 MHz, Chloroform-d) δ 7.17-7.10(m, 4H), 6.76-6.57 (m, 1H), 2.87-2.68 (m, 1H), 2.61-2.54 (m, 2H),2.47-2.16 (m, 3H), 1.96 (ddd, J=10.2, 5.2, 2.7 Hz, 1H), 1.77-1.60 (m,3H), 1.30-1.24 (m, 13H), 0.96 (t, J=7.3 Hz, 3H).

Compound 121 was prepared from (S)-tert-butyl3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateINT-17 using General Procedure 8 followed by General Procedure 10 using4,4,5,5-tetramethyl-2-(4′-propyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yl)-1,3,2-dioxaborolane.

Compound 122 was prepared from (S)-tert-butyl3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateINT-17 using General Procedure 8 followed by General Procedure 10 using2-(4′,4′-dimethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-((1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoicacid (Compound 123)

Prepared using General Procedure 10: To a stirred solution of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid (6.13 g, 12.55 mmol) and racemic4,4,5,5-tetramethyl-2-((1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)-1,3,2-dioxaborolane(4.20 g, 13.81 mmol) in dioxane (100 mL) was added a solution of NaHCO₃(3.16 g, 37.7 mmol) in water (50 mL). This mixture was warmed to 40° C.then de-gassed and treated with PdCl₂dppf (0.276 g, 0.377 mmol). Themixture was heated under gentle reflux. After 3 h, the mixture wasallowed to cool, diluted with water (100 mL) and DCM (200 mL) thenacidified with AcOH. The layers were separated and the aqueous furtherextracted with DCM (2×100 mL). Solvents were evaporated and the residuepurified by column chromatography (AcOH/EA/THF/DCM/iso-hexanes). Theproduct was re-slurried from MeOH to afford 4.57 g (62%) of a mixture ofdiastereomers(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-((1RS,1′r,4′RS)-4′-methyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoicacid. LCMS-ESI (m/z) calculated for C₃₅H₄₃N₃O₃S: 585.3; no m/z observed,t_(R)=11.12 min (Method 10). Chiral analysis (Chiral Method 1)showed >95% single peak. ¹H NMR (400 MHz, DMSO-d₆) δ 12.84 (s, 1H), 8.91(s, 2H), 8.64 (d, J=8.3 Hz, 1H), 8.27 (d, J=8.3 Hz, 2H), 7.63 (d, J=3.9Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 6.92 (d, J=3.9 Hz, 1H), 6.44 (s, 1H),4.80-4.42 (m, 1H), 3.25 (dd, J=13.9, 4.5 Hz, 1H), 3.10 (dd, J=13.9, 10.5Hz, 1H), 2.55-2.51 (m, 2H), 2.41-2.26 (m, 2H), 2.00-1.92 (m, 2H),1.85-1.62 (m, 4H), 1.39-1.28 (m, 11H), 1.16-0.70 (m, 8H).

Compound 124 was prepared from (S)-tert-butyl3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateR-INT-17 using General Procedures 8, 7, 4 and4,4,5,5-tetramethyl-2-(4′-propyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yl)-1,3,2-dioxaborolanein step 10 sequentially.

Compound 125 was prepared from compound 76 using General Procedure 18.

TABLE 1 Representative Compounds LCMS RE- COM- TEN- PURI- POUND TION TYNUM- TIME METH- STRUCTURE BER (min) OD

 1 12.15 11

 2 11.09 14

 3 13.30 14

 4 12.55 14

 5 12.98 14

 6 11.38 14

 7 11.84 14

 8 11.80 14

 9 11.57 14

 10  8.36 14

 11  8.20 14

 12 11.18 14

 13 11.36 14

 14 11.54 14

 15 10.83 14

 16 10.92 14

 17 11.16 14

 18  9.85 14

 19 10.03 14

 20 10.65 14

 21 10.80 14

 22 11.30 14

 23 11.70 14

 24 10.90 14

 25 11.10 14

 26 11.30 14

 27 10.89 14

 28 10.65 14

 29 10.76 14

 30 10.07 14

 31 10.62 14

 32 11.76 14

 33 10.61 14

 34 10.60 14

 35 11.14 14

 36  9.61 10

 37  7.90 10

 38 10.40 10

 39  9.30 10

 40  9.20 10

 41  9.35 10

 43  7.44 10

 44 11.03 10

 45  9.95 10

 46  4.93 10

 47 10.15 10

 48  8.72 10

 49  7.35 10

 50  8.08 10

 51  9.04 10

 52  9.59 10

 53 10.60 10

 54  7.98 10

 55  8.50 10

 56  9.79 10

 57  8.85 10

 58  9.32 10

 59  9.73 10

 60  8.58 10

 61  6.59 10

 62  7.04 10

 63  7.65 10

 64  7.53 10

 65  8.12 10

 66  6.48 10

 67 11.72 10

 69  7.60 10

 70 11.79 10

 71 11.56 14

 72 11.08 14

 73 11.08 14

 74 11.27 14

 75 11.80 14

 76 11.50 10

 77 11.57 10

 78 11.40 14

 79 12.18 14

 80 12.30 14

 81 11.83 14

 82  8.67 10

 83  9.68 10

 84  9.20 10

 85 12.21 10

 86 12.01 10

 87 12.11 10

 88  9.46 10

 89  9.88 20

 90 10.60 10

 91  8.19 20

 92  8.39 20

 93  8.57 28

 94  9.24 20

 95  9.16 20

 96  9.20 20

 97  8.44 20

 98  8.83 20

 99  7.97 20

100  8.80 20

101  9.59 20

102  9.39 20

103  8.85 20

104  8.66 20

105  9.50 28

106  9.32 28

107  9.65 28

108 12.55 28

109  9.62 28

110  9.56 28

111  9.48 28

112  9.01 28

113  9.94 28

114 12.32 28

115  9.32 28

116  9.71 28

117 10.75 10

118 11.43 10

119  4.38 14

120 11.34 10

121 10.79 10

122 12.01 10

123 11.12 10

124 11.95 10

125  9.57 28

Biological Assays

Assay Procedures

GLP-1 PAM Shift cAMP Assay: Dose Response of Peptide Ligand in Presenceof Fixed Concentration of Compound.

A GLP-1R expressing CRE-bla CHO-K1 cell line was purchased fromInvitrogen. Cells were seeded into 384-well white flat bottom plates at5000 cells/well/20 μL growth media (DMEM-High glucose, 10% dialyzed FBS,0.1 mM NEAA, 25 mM Hepes, 100 U/mL penicillin/100 μg/mL streptomycin, 5μg/mL Blasticidin, 600 μg/mL Hygromycin) and incubated for 18 h at 37°C. in 5% CO₂. Growth medium was replaced with 12 μL assay buffer (HanksBalanced Salt solution, 10 mM Hepes, 0.1% BSA, pH 7.4). A 5× peptidedose response curve (12-point) was generated in assay buffer containing1.5 mM IBMX, 12.5% DMSO, and 50 μM compound. Peptide ligand wasGLP-1(9-36). The 5× peptide dose response plus compound mix was added (3μL) and cells were incubated for 30 min at 37° C. Direct detection ofcAMP was carried out using DiscoveRx HitHunter cAMP kit according tomanufacturer's instructions and luminescence was read using a SpectraMaxM5 plate reader. Luminescence was analyzed by non-linear regression todetermine the EC₅₀ and Emax. A GLP-1(7-36) dose response was included todetermine maximum efficacy.

EC₂₀ GLP-1(9-36) PAM cAMP Assay: Dose Response of Compound in thePresence of Fixed Concentration of GLP-1 (9-36).

GLP-1R CRE-bla CHO-K1 cells cultured in growth medium (DMEM-Highglucose, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM Hepes, 100 U/mLpenicillin/100 μg/mL streptomycin, 5 μg/mL Blasticidin, 600 μg/mLHygromycin) were trypsinized and plated in suspension into 384 wellwhite flat bottom plates at 5000 cells/well in 12 μL assay buffer (HanksBalanced Salt solution, 10 mM Hepes, 0.1% BSA, pH 7.4). A 5× compounddose response curve (12-point) was generated in assay buffer containing1.5 mM IBMX, 4% DMSO. GLP-1(9-36) was diluted to 4.2 μM in assay buffercontaining 1.5 mM IBMX and 4% DMSO. The 5× compound dose response wasadded (3 μL), followed by 0.5 μL of GLP-1(9-36) and cells were incubatedfor 30 min at 37° C. Direct detection of cAMP was carried out usingDiscoveRx HitHunter cAMP kit according to manufacturer's instructionsand luminescence was read using a SpectraMax M5 plate reader.Luminescence was converted to total cAMP using a cAMP standard curve anddata was analyzed by non-linear regression to determine the EC₅₀ andEmax.

Peptide Sequences

GLP-1(7-36): HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂. GLP-1(9-36):EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂. GLP-1(7-36) was purchased fromGenScript. GLP-1(9-36) was purchased from Biopeptide Co., Inc.

GLP-1 Activity

Activity data for representative GLP-1 modulators are displayed in Table2. The EC₂₀GLP-1(9-36) PAM Activity range is denoted as follows: +denotes activity <0.5 μM, ++ denotes activity between 0.5 and 2.5 μM,+++ denotes activity between 2.5 and 5 μM, and ++++ denotes activity 5to 10 μM.

TABLE 2 GLP-1 Activity COMPOUND EC₂₀ GLP-1(9-36) NUMBER PAM EC₅₀ 1 + 2++++ 3 + 4 + 5 ++ 6 + 7 + 8 + 9 ++ 10 + 11 + 12 +++ 13 + 14 + 15 + 16 ++17 + 18 ++++ 19 ++ 20 ++++ 21 + 22 + 23 + 24 + 25 +++ 26 + 27 + 28 ++++29 ++ 30 ++ 31 + 32 + 33 ++ 34 + 35 ++ 36 + 37 ++ 38 ++ 39 ++ 40 ++ 41++++ 43 ++++ 44 + 45 ++ 46 +++ 47 + 48 ++ 49 ++++ 50 ++ 51 ++ 52 ++ 53++ 54 ++++ 55 +++ 56 + 57 ++ 58 +++ 59 + 60 ++ 61 + 62 + 63 ++ 64 +++ 65++ 66 +++ 67 + 69 +++ 70 + 71 + 72 +++ 73 + 74 + 75 ++ 76 + 77 + 78 ++79 + 80 ++ 81 ++ 82 ++ 83 + 84 + 85 + 86 + 87 + 88 + 89 + 90 + 91 + 92 +93 + 94 + 95 ++ 96 + 97 + 98 + 99 ++ 100 + 101 + 102 ++ 103 + 104 +105 + 106 + 107 + 108 ++ 109 + 110 + 111 + 112 + 113 + 114 ++ 115 +116 + 117 + 118 + 119 ++ 120 ++ 121 + 122 ++ 123 + 124 ++ 125 ++

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet, areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments. These and other changes can be made to the embodiments inlight of the above-detailed description. In general, in the followingclaims, the terms used should not be construed to limit the claims tothe specific embodiments disclosed in the specification and the claims,but should be construed to include all possible embodiments along withthe full scope of equivalents to which such claims are entitled.Accordingly, the claims are not limited by the disclosure.

We claim:
 1. A method for treating a condition for which increasing fatty acid oxidation, decreasing lipogenesis, and/or improving hepatic glucose metabolism provides a beneficial effect to a patient, comprising administering an effective amount of a compound to the patient at a frequency and for a duration of time sufficient to provide the beneficial effect, the compound having the structure of Formula I-R or I-S:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof wherein A is pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl, each of which may be optionally substituted with one or more of R₄; B is phenyl or heterocycle; C is a nonaromatic carbocyclyl or nonaromatic carbocyclylalkyl; each R₁ is independently H or C₁₋₄ alkyl; R₂ is OH, —O—R₈, —N(R₁)—SO₂—R₇, —NR₄₁R₄₂, —N(R₁)—(CR_(a)R_(b))_(m)—COOR₈, —N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)(R₄₀), —N(R₁)—(CR_(a)R_(b))_(m)—N(R₁)C(O)O(R₈), —N(R₁)—(CR_(a)R_(b))_(m)—N(R₁)(R₄₀), —N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl, or —N(R₁)—(CR_(a)R_(b))_(m)-heterocyclyl, which heterocyclyl may be optionally (singly or multiply) substituted with R₇; each R₃ and R₄ is independently H, halo, alkyl, alkyl substituted (singly or multiply) with R₃₁, alkoxy, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, aryl, heterocyclyl, —OH, —OR₇, —CN, —NO₂, —NR₁R₇, —C(O)R₇, —(O)NR₁R₇, —NR₁C(O)R₇, —SR₇, —S(O)R₇, —S(O)₂R₇, —OS(O)₂R₇, —S(O)₂NR₁R₇, —NR₁S(O)₂R₇, —(CR_(a)R_(b))_(m)NR₁R₇, —(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₇, —(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₇ or —(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)COOR₈; or any two R₃ or R₄ groups on the same carbon atom taken together form oxo; R₅ is R₇, —(CR_(a)R_(b))_(m)—(CR_(a)R_(b))_(m)—R₇, or -(-L₃-(CR_(a)R_(b))_(r)-L₃-R₇, wherein the carbon atoms of any two adjacent —(CR_(a)R_(b))_(m) or (CR_(a)R_(b))_(r) groups may be taken together to form a double bond (—(C(R_(a))═(C(R_(a))—) or triple bond (—C≡C—); R₆ is H, alkyl, aryl, heteroaryl, heterocyclyl, heterocycloalkyl, any of which may be optionally substituted (singly or multiply) with R₇ or —(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₇; each R₇ is independently R₁₀; a ring moiety selected from cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl, where such ring moiety is optionally (singly or multiply) substituted with R₁₀; or when a carbon atom bears two R₇ groups such two R₇ groups are taken together to form oxo or thioxo, or are taken together to form a ring moiety selected from cycloalkyl, aryl, heterocyclyl or heterocyclylalkyl, wherein such ring moiety is optionally singly or multiply substituted with R₁₀; each R₈ is independently H, alkyl, haloalkyl, aryl, —(CR_(a)R_(b))_(m)-L₂-(CR_(a)R_(b))_(m)—R₁ or -(-L₃-(CR_(a)R_(b))_(r))_(s)-L₃-R₁; each R₁₀ is independently H, halo, alkyl, haloalkyl, haloalkoxy, perhaloalkyl, perhaloalkoxy, —(CR_(a)R_(b))_(m)OH, —(CR_(a)R_(b))_(m)OR₈, —(CR_(a)R_(b))_(m)CN, —(CR_(a)R_(b))_(m)NH(C═NH)NH₂, —(CR_(a)R_(b))_(m)NR₁R₈, —(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈, —(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₈, —(CR_(a)R_(b))_(m)C(O)R₈, —(CR_(a)R_(b))_(m)C(O)OR₈, —(CR_(a)R_(b))_(m)C(O)NR₁R₈, —(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)C(O)OR₈, —(CR_(a)R_(b))_(m)NR₁C(O)R₈, —(CR_(a)R_(b))_(m)C(O)NR₁S(O)₂R₈, —(CR_(a)R_(b))_(m)SR₈, —(CR_(a)R_(b))_(m)S(O)R₈, —(CR_(a)R_(b))_(m)S(O)₂R₈, —(CR_(a)R_(b))_(m)S(O)₂NR₁R₈ or —(CR_(a)R_(b))_(m)NR₁S(O)₂R₈; each R₃₁ is independently H, halo, hydroxyl, —NR₄₁R₄₂, or alkoxy; each R₄₀ is independently H, R₇, alkyl which may be optionally (singly or multiply) substituted with R₇, or R₄₀ and R₁ taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl which may be optionally (singly or multiply) substituted with R₇; each R₄₁ and R₄₂ is independently R₄₀, —(CHR₄₀)_(n)—C(O)O—R₄₀, —(CHR₄₀)_(n)—C(O)—R₄₀, —(CH₂)_(n)—N(R₁)(R₇), aryl or heteroaryl any of which aryl or heteroaryl may be optionally (singly or multiply) substituted with R₇; or any two R₄₁ and R₄₂ taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl which may be optionally (singly or multiply) substituted with R₇; each R_(a) and R_(b) is independently H, halo, alkyl, alkoxy, aryl, aralkyl, heterocyclyl, heterocyclylalkyl (any of which alkyl, alkoxy, aryl, aralkyl, heterocyclyl or heterocyclylalkyl may be optionally (singly or multiply) substituted with R₇), —(CHR₄₀)_(m)C(O)OR₄₀, —(CHR₄₀)_(m)OR₄₀, —(CHR₄₀)_(m)SR₄₀, —(CHR₄₀)_(m)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)N(R₁)(CHR₄₀)_(m)C(O)NR₄₁R₄₂, —(CHR₄₀)_(m)C(O)N(R₁)—(CHR₄₀)_(m)C(O)OR₄₀, or —(CHR₄₀)_(m)—S—S—R₄₀; or any two R_(a) and R_(b) taken together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl optionally substituted (singly or multiply) with R₇; or R₁ and any one of R_(a) or R_(b) taken together with the atoms to which they are attached form heterocyclyl optionally substituted (singly or multiply) with R₇; L₂ is independently, from the proximal to distal end of the structure of Formula I-R or I-S, null, —O—, —OC(O)—, —NR₁—, —C(O)NR₁—, —N(R₁)—C(O)—, —S(O₂)—, —S(O)—, —S—, —C(O)— or —S(O₂)—N(R₁)—; each L₃ is independently null, —O—, or —N(R₁)— each m is independently 0, 1, 2, 3, 4, 5 or 6; each n is independently 0 or 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; each r is independently 2, 3, or 4; and each s is independently 1, 2, 3, or
 4. 2. The method of claim 1, the compound having one of the following structures:


3. The method of claim 1, the compound having one of the following structures:


4. The method of claim 1, the compound having one of the following structures:


5. The method of claim 1 wherein B is pyrimidinyl, pyrazolyl, pyridinyl or indolyl.
 6. The method of claim 1 wherein C is nonaromatic carbocyclyl.
 7. The method of claim 6 wherein nonaromatic carbocyclyl is cycloalklyl.
 8. The method of claim 6 wherein nonaromatic carbocyclyl is cycloalkenyl.
 9. The method of claim 6 wherein C is:


10. The method of claim 1, the compound having one of the following structures:


11. The method of claim 10 wherein R₁ is H.
 12. The method of claim 10 wherein R₄ is H.
 13. The method of claim 10 wherein q is one.
 14. The method of claim 13 wherein R₅ is alkyl.
 15. The method of claim 13 wherein p is one.
 16. The method of claim 15 wherein R₃ is alkyl.
 17. The method of claim 16 wherein alkyl is a straight or branched alkyl.
 18. The method of claim 16 wherein alkyl is cycloalky.
 19. The method of claim 1, the compound having one of the following structures:


20. The method of claim 1, the compound having one of the following structures:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 21. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 22. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 23. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 24. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 25. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 26. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 27. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 28. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 29. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 30. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 31. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 32. The method of claim 1, the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.
 33. The method of any one of claims 1 or 20-32, wherein the condition is non-alcoholic fatty liver disease (NAFLD).
 34. The method of any one of claims 1 or 20-32, wherein the condition is non-alcoholic steatohepatitis (NASH). 